Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Regulation of Cell Survival Mechanisms in Alzheimer's Disease by Glycogen Synthase Kinase-3

Regulation of Cell Survival Mechanisms in Alzheimer's Disease by Glycogen Synthase Kinase-3 SAGE-Hindawi Access to Research International Journal of Alzheimer’s Disease Volume 2011, Article ID 861072, 11 pages doi:10.4061/2011/861072 Review Article Regulation of Cell Survival Mechanisms in Alzheimer’s Disease by Glycogen Synthase Kinase-3 Marjelo A. Mines, Eleonore Beurel, and Richard S. Jope Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Sparks Center 1057, 1720 Seventh Avenue South, Birmingham, AL 35294-0017, USA Correspondence should be addressed to Richard S. Jope, jope@uab.edu Received 15 January 2011; Accepted 9 March 2011 Academic Editor: Adam Cole Copyright © 2011 Marjelo A. Mines et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A pivotal role has emerged for glycogen synthase kinase-3 (GSK3) as an important contributor to Alzheimer’s disease pathology. Evidence for the involvement of GSK3 in Alzheimer’s disease pathology and neuronal loss comes from studies of GSK3 overexpression, GSK3 localization studies, multiple relationships between GSK3 and amyloid β-peptide (Aβ), interactions between GSK3 and the microtubule-associated tau protein, and GSK3-mediated apoptotic cell death. Apoptotic signaling proceeds by either an intrinsic pathway or an extrinsic pathway. GSK3 is well established to promote intrinsic apoptotic signaling induced by many insults, several of which may contribute to neuronal loss in Alzheimer’s disease. Particularly important is evidence that GSK3 promotes intrinsic apoptotic signaling induced by Aβ. GSK3 appears to promote intrinsic apoptotic signaling by modulating proteins in the apoptosis signaling pathway and by modulating transcription factors that regulate the expression of proteins involved in apoptosis. Thus, GSK3 appears to contribute to several neuropathological mechanisms in Alzheimer’s disease, including apoptosis-mediated neuronal loss. 1. Introduction 2. Overview of Cell Death in Alzheimer’s Disease Ten years ago we first noted that glycogen synthase kinase-3 (GSK3) appeared to be linked to all of the major pathological Among the known mechanisms that may contribute to mechanisms that had been identified in Alzheimer’s disease loss of neurons in Alzheimer’s disease brain, apoptosis has [1]. Since then, a remarkable amount of new evidence has received the most attention. Apoptotic signaling is generally solidified the central role of GSK3 in Alzheimer’s disease neu- classified as proceeding by either an intrinsic pathway or an ropathology, as exemplified by this entire issue being devoted extrinsic pathway. Of these, the intrinsic apoptotic signaling to the subject. Among the early identified links between pathway has predominated in studies of Alzheimer’s disease. GSK3 and Alzheimer’s disease was the discovery that GSK3 Intrinsic apoptotic signaling is most often induced by promotes the intrinsic apoptotic signaling pathway that may intracellular damage that leads to mitochondrial release of be partly responsible for neuronal loss in Alzheimer’s disease cytochrome c and the activation of intracellular cysteine [2]. Here we review the multiple cellular pathways influenced proteases called caspases [3], particularly caspase-9 and by GSK3 that may contribute to changes in cell viability in caspase-3, with a variety of other pro-apoptotic media- Alzheimer’s disease. tors and caspases contributing to the eventual outcome 2 International Journal of Alzheimer’s Disease of apoptosis [4]. Extrinsic apoptotic signaling is initiated greatly increased by modestly elevated levels of GSK3β, by stimulation of plasma membrane death receptors that demonstrating that increased GSK3 activity promotes apop- initiate apoptosis by activation of caspase-8, and subsequent totic signaling induced by a variety of toxic agents [7]. These apoptotic signaling can proceed through the mitochondrial and other in vitro studies demonstrating that increased GSK3 pathway or independently of mitochondria by caspase-8- activity can promote activation of the intrinsic apoptotic mediated direct activation of caspase-3 [5]. Of these two signaling pathway and that inhibition of GSK3 provides apoptotic signaling pathways, the intrinsic system has been protection from apoptosis have been previously reviewed in the focus of the great majority of studies of apoptotic cell detail [1, 2]. death mechanisms in Alzheimer’s disease. The results of in vitro studies that showed promotion of intrinsic apoptotic signaling by GSK3 raised the question of whether abnormal increases in GSK3 in vivo may contribute 3. GSK3 Promotes Intrinsic Apoptotic Signaling to neuronal death in neurodegenerative diseases, such as Alzheimer’s disease. One approach to test this that has Much evidence indicates that promotion of the intrinsic been productive is to study transgenic mice over-expressing apoptotic signaling pathway by GSK3 may be particularly GSK3. Spittaels and colleagues [8] studied transgenic mice important in the apoptosis and neuronal loss that occurs in over-expressing constitutively active S9A-GSK3β and found Alzheimer’s disease. This is because GSK3 has been shown hyperphosphorylation of the microtubule-associated protein to promote apoptosis following a wide range of insults tau and altered behaviors in sensorimotor tasks in these that activate the intrinsic apoptotic signaling pathway [2]. mice. Mice postnataly over-expressing S9A-GSK3β driven by In order to promote intrinsic apoptotic signaling, GSK3 the thy-1 promoter in neurons exhibited decreased brain must be active. The major mechanism regulating GSK3 volume and cell size, increased neuronal densities, and activity is phosphorylation of an N-terminal serine in learning deficits in the Morris water maze [9]. Lucas and col- each of the two paralogs (commonly called isoforms) of leagues [10] created transgenic mice over-expressing GSK3β GSK3, serine9-GSK3β or serine21-GSK3α. Phosphorylation in regions specifically relevant to Alzheimer’s disease, the of these regulatory serines inhibits GSK3, thus signaling hippocampus and neuronal layers I–VI of the cortex. These activities that reduce GSK3 serine-phosphorylation activate mice displayed evidence of apoptosis activation, including GSK3. The inhibitory serines in GSK3 can be phosphorylated increased TUNEL staining and caspase-3 activation in the by several different kinases. The most often studied of these dentate gyrus [10]. Concomitant with increased markers is Akt (also called protein kinase B), which itself is activated of apoptosis, the GSK3β-over-expressing mice exhibited by multiple receptor-coupled signaling pathways that signal activated astrocytes and microglia. These mice also displayed through phosphatidylinositol 3-kinase (PI3K), such as sig- deficits in learning in the Morris water maze, but tau naling induced by a variety of neurotrophin receptors. Thus, filaments were concluded to not be involved in the learning one mechanism by which GSK3 can be activated is by signals deficits [11]. Further studies of these mice took advan- that reduce its serine-phosphorylation mediated by Akt or tage of the capability of terminating GSK3β overexpression other kinases. A widely used method to study the actions with doxycyclin treatment, which reduced GSK3β levels, of GSK3β is to express GSK3β with a serine9-to-alanine9 reduced tau phosphorylation, increased microtubule poly- mutation (S9A-GSK3β) to maintain expressed GSK3β fully merization, reduced reactive astrocytosis, restored spatial active. GSK3 also must be phosphorylated on a tyrosine memory, and decreased levels of active caspase-3 [12]. When residue for full activity, tyrosine216-GSK3β or tyrosine279- the tetracycline-regulated conditional transgenic mice were GSK3α. Although the mechanisms regulating tyrosine- crossed with mice over-expressing tau carrying a FTDP-17 phosphorylation of GSK3 are still not well-understood, a mutation, GSK3-mediated hyperphosphorylated tau had an number of reports have indicated that GSK3 activity can be increased propensity to form filaments, leading to neurofib- increased by signals that increase tyrosine-phosphorylated rillary tangles (NFTs), and displayed microencephaly at 18 GSK3. months of age [13]. Expression of constitutively active S9A- GSKβ in the cortex and hippocampus caused hyperphos- 3.1. Overexpression of GSK3 Is Sufficient to Activate Apoptosis. phorylated tau, neurofibrillary tangles, and morphological changes in neuronal structure [14]. Mice expressing human Overexpression of GSK3 in cells or rodent brains has been shown to induce apoptosis and neuronal death in many P301L tau (JNLP3 mice), expressing mutant amyloid pre- reports. The first study of this type showed that that transient cursor protein (Tg2576 mice), and expressing both P301L tau mutationand mutant APPprotein (TAPPmice),all overexpression of wild-type GSK3β was sufficient to induce apoptosis in cultured PC12 cells [6]. Furthermore, this report displayed increased tyrosine-phosphorylated GSK3α/β in showed that expression of a dominant-negative kinase-dead spinal cord and amygdala neurons characterized by gran- mutant of GSK3β was sufficient to reduce apoptosis that ulovacular degenerative granules and neurofibrillary tangles was induced by inhibition of PI3K, demonstrating that in the JNPL3 and TAPP mice [15]. Avila and colleagues [16] reported that mice over-expressing GSK3β had a 2-fold GSK3 is a major mediator of apoptosis in conditions of reduced PI3K activity [6]. Bijur and colleagues [7]extended increase in tau levels and a decrease in dentate gyrus volume, those findings to show that although relatively low levels of and suggested that increased GSK3β activity, particularly in the dentate gyrus, hinders neurogenesis, thereby promoting over-expressed GSK3β did not induce apoptosis in human neuroblastoma SH-SY5Y cells, pro-apoptotic signaling was the decreased tissue volume. Collectively, these findings in International Journal of Alzheimer’s Disease 3 transgenic mice indicate that GSK3 promotes pathological tissues. Increases in GSK3 immunoreactivity co-localized process associated with Alzheimer’s disease, but whether specifically with granulovacular degenerative granules, and GSK3 promoted decreases in neuronal viability often was there were no detectable changes in GSK3 immunoreactivity not directly investigated due to the difficulty in capturing within neurofibrillary tangles. Ferrer and colleagues [19]also transient markers of apoptosis in in vivo studies. reported increased GSK3 immunoreactivity in granulovacu- lar degenerative bodies located in neuronal cell bodies, and also found increased GSK3 immunoreactivity in glial cells in 3.2. Localization of GSK3 in Alzheimer’s Disease Brain. postmortem human brain tissues. Localization studies in postmortem Alzheimer’s disease brain have been used to determine if GSK3 is accumulated or activated in areas with prominent neurodegeneration. Pei 3.3. Toxicity Associated with Amyloid-β Peptide (Aβ). Sub- and colleagues [17] reported increased GSK3α and GSK3β stantial evidence has demonstrated that Aβ activates GSK3 immunoreactivities in plaques and CA1 hippocampal neu- by decreasing its inhibitory serine-phosphorylation, which rons, and co-staining with Congo red indicated that many appears to contribute to Aβ-induced increased tau phos- cells with increased GSK3β immunoreactivity contained phorylation and to Aβ-induced neurotoxicity [21–30]. These hyperphosphorylated tau and neurofibrillary tangles. Sub- studies showing Aβ-induced activation of GSK3 have used sequently, Pei and colleagues [18] compared non-diseased a variety of peptides, including Aβ ,Aβ ,and the 1–40 1–42 brains, deemed Stage 0 cases, to Alzheimer’s disease-like 25–35 peptide fragment, indicating that accumulation of brains from middle-aged and senescent patients, classified as any of these may activate GSK3, although perhaps by stages A–C according to the extent of amyloid deposition, utilizing different signaling mechanisms, which remain to and NF I–VI according to the extent of neurofibrillary be identified. Takashima and colleagues [21–24, 31]first tangle pathology. They found only moderate active GSK3β identified a neuroprotective effect of inhibiting GSK3 (at that staining in normal brains (Stage 0) in neurons of the time also called tau protein kinase-1) against Aβ-induced entorhinal cortex and CA1 and CA2 regions of the hip- toxicity. They found that in cultured rat hippocampal pocampus [18]. Inactive GSK3β staining was pronounced neurons Aβ treatment increased GSK3β activity and pre- in entorhinal cortical neurons and the hippocampal CA1 treatment with GSK3β antisense oligonucleotides prevented region relative to staining for active GSK3. Stage 0/NF I-II Aβ-induced cell death and reduced tau phosphorylation. brains also had increased inactive GSK3β, relative to active These studies indicated that GSK3 is involved in Aβ-induced GSK3, immunoreactivity in the entorhinal cortex and hip- tau phosphorylation and neurotoxicity. Subsequent reports pocampal CA1 region. Stage III/IV brains showed increased also demonstrated that inhibitors of GSK3, such as lithium tau phosphorylation immunoreactivity (AT8 antibody) and or SB216763, reduced Aβ-induced tau phosphorylation and tangle formation in the entorhinal cortex and hippocam- cell death in cultured neurons [27, 29, 32]. Inestrosa and pal CA1 region, and tangle-containing neurons also had colleagues [33] found that treatment with lithium pre- increased active, as well as inactive, GSK3 immunoreactivity, vented Aβ -induced morphological changes, specifically 1−42 suggesting increases in both GSK3 levels and activity as shrunken soma and affected dendritic and axonal processes, disease pathology progressed. Stage V/VI brains exhibited and reduced Aβ-induced decreases in cell viability of primary AT8 immunoreactivity and tangle inclusions throughout rat hippocampal neuronal cultures [33]. After injection of the entorhinal and temporal cortices and the hippocampus. Aβ into rat hippocampus, increased GSK3 immunoreactivity Most inclusion-positive neurons stained intensely for active was found near Aβ deposits [33]. Treatment with SB216763 GSK3, while little or no inactive GSK3 immunoreactivity was or GSK inhibitor VIII also prevented Aβ-induced caspase-3 recorded in cortical or hippocampal tissues. Collectively, Pei activation in vivo, decreased TUNEL positive neurons, pre- and colleagues [18] clearly defined an Alzheimer’s disease vented tau-phosphorylation, reduced microglia activation, progression profile detailing increased tau phosphorylation decreased cytochrome c release from the mitochondria to and increased GSK3β expression and activity in cortical the cytosol, and improved deficits in the Morris water maze and hippocampal tissues as disease pathology worsened. [27, 28]. GSK3 inhibitor VIII or lithium reduced Aβ - 1–42 Ferrer and colleagues [19] also found increased GSK3 induced reduction in cell viability and reduced markers immunoreactivity in degenerating neurons characterized by of apoptosis [28]. Lithium treatment decreased cortical tangle-like inclusions in Stage III and Stage VI postmortem tau phosphorylation and aggregates, and reduced axonal Alzheimer’s disease entorhinal cortex and hippocampus. degeneration [34]. Administration of the GSK3 inhibitor Furthermore, GSK3 colocalized with 40–80% of neurons NP12 decreased tau phosphorylation, decreased Aβ deposi- with hyperphosphorylated tau (PHF-1 antibody), thereby tion, and improved performance in the Morris water maze supporting the notion that GSK3 expression and/or activity in amyloid precursor protein (APP) transgenic mice, and increases as Alzheimer’s disease progresses. reduced neuronal loss in the CA1 region of the hippocampus GSK3 immunoreactivity has been reported to be in- and the entorhinal cortex [35]. Rockenstein and colleagues creased at sites of granulovacular degeneration, a patho- [36] also reported neuroprotective effects of inhibiting GSK3 logical characteristic of Alzheimer’s disease [15, 19, 20]. with lithium using APP transgenic mice, with improvements Leroy and colleagues [20] reported increased GSK3β and in the Morris water maze task, decreased Aβ immunore- phospho-tyr216-GSK3β immunoreactivity in neuronal cell activity, decreased phospho-tau immunoreactivity, and an bodies and dendrites of postmortem human hippocampal increase in MAP2 staining (indicative of increased neuron 4 International Journal of Alzheimer’s Disease density) after treatment with lithium. The role of GSK3 was increased caspase-3 activation [49]. In HEK293 and SK- further examined by crossing mice conditionally expressing N-MC cells, Kwok and colleagues [50] transiently over- a dominant-negative (DN) GSK3β construct with hAPP expressed GSK3βΔexon9+11, which lacks exons 9 and 11 and transgenic mice. These hAPP x DN-GSK3β mice displayed is characterized by an increased propensity to phosphorylate improved performance in the Morris water maze, increased tau, and found decreased β-catenin levels and signaling. MAP2 immunoreactivity, decreased Aβ immunoreactivity, Transient transfection of tau decreased β-catenin levels decreased phospho-tau immunoreactivity, and normal cell by 25%, and co-expression of tau and GSK3βΔexon9+11 morphologies, when compared to hAPP transgenic litter- reversed the GSK3-mediated decrease in β-catenin signal- mates, suggesting that inhibition of GSK3 can phenotypically ing. Inestrosa and colleagues have reported in detail that rescue hAPP mice [36]. Ma and colleagues [37] showed that activation of Wnt signaling, which inhibits GSK3-mediated antibodies directed against Aβ increased inhibitory serine- phosphorylation and degradation of β-catenin, is neuro- phosphorylation of GSK3, which was associated with a protective against Aβ toxicity [33, 51–53]. Thus, reduced decrease in neurotoxicity. Altogether, these and additional levels of Wnt signalling-associated β-catenin may contribute reports have firmly established that Aβ activates GSK3 and to GSK3-mediated neurotoxicity induced by Aβ produc- that reducing GSK3 activity provides protection from Aβ- tion and promoted by mutations in PS1 in Alzheimer’s induced neurotoxicity. disease. Studies of the mechanism by which Aβ activates GSK3 have indicated the involvement of the PI3K-Akt 3.4. Toxicity Associated with Tau. The microtubule-associat- pathway, which normally maintains inhibitory serine- ed protein tau is one of the most well characterized substrates phosphorylation of GSK3. Aβ treatment was shown to cause of GSK3 [54]. Phosphorylation of tau by GSK3 promotes tau time-dependent decreases in PI3K activity and increases dissociation from microtubules, increasing destabilization of in GSK3 activity [22]. Treatment of cultured cells with microtubules [55]. Conversely, inhibition of GSK3 promotes Aβ reduced Akt phosphorylation, indicative of decreased 1–42 tau binding to microtubules and assembly of microtubules Akt activity [38, 39], activated GSK3β [38], and activated [56]. As noted above, several studies have reported that caspase-3 [25], suggesting that decreased Akt activity con- the GSK3-mediated increase in tau phosphorylation in tributes to Aβ-induced activation of GSK3, which promotes Alzheimer’s disease may result in part from Aβ-induced apoptosis. activation of GSK3. GSK3-mediated tau phosphorylation In addition to acting downstream of Aβ in its neurotoxic in Alzheimer’s disease has been suggested to promote tau signaling, GSK3 likely also influences the neurotoxicity of oligomerization, which can be toxic [57, 58], and aggregation Aβ by regulating APP processing and the production of Aβ. of tau and eventual neurodegeneration [54, 59]. Sahara Takashima and colleagues [24]found that GSK3β associated and colleagues [60] reported that overexpression of tau in with presenilin-1 in postmortem Alzheimer’s disease cortical SH-SY5Y cells resulted in increased tau phosphorylation tissues and in COS-7 cells transiently transfected with wild- and increased caspase-3 activity, suggesting a role in pro- type presenilin-1, which raised the possibility that GSK3 apoptotic signaling and cell death. It is possible that GSK3β- may regulate Aβ production. This was found in studies that mediated hyperphosphorylation of tau may promote tau- showed reducing GSK3 activity in vitro or in vivo diminished mediated, as well as Aβ-mediated, neurotoxicity. the production of Aβ [40–42]. The mechanism by which GSK3 promotes Aβ production remains to be determined, Transgenic mice have also been used to study the inter- but may be related to its phosphorylation and regulation of actions between tau and GSK3. Using protein preparations presenilin-1 [24, 43]or of APP [44]. from the brains and spinal cords of double transgenic mice β-Catenin destabilization has been suggested to be a over-expressing GSK3β and human tau40-1, an isoform of contributing factor in Aβ-induced GSK3-mediated neuro- tau containing an additional 29 and 58 amino acid sequence toxicity. GSK3 promotes the degradation of β-catenin, and that promotes Alzheimer’s disease-like pathologies [61], nuclear β-catenin levels were decreased in response to acute Spittaels and colleagues [8] found decreased tau binding Aβ treatments, indicating that Aβ-induced activation of to microtubules in double transgenic mice, as compared GSK3 led to increased degradation of β-catenin [45, 46]. to transgenic mice littermates expressing human tau40-1 Lucas and colleagues [10] reported decreased nuclear β- alone. The relationship between GSK3 and tau was found catenin levels in GSK3 over-expressing mice. Presenilin- to be more than a mere protein-protein interaction, as 1 (PS1), a GSK3 substrate, can regulate the turnover of Kwok and colleagues [50] found interactions between the β-catenin [47, 48]. Kang and colleagues [48]found that GSK3β and tau (MAPT) genes associated with increased GSK3 co-immunoprecipitated with PS1 but not with mutant risk and incidence of Alzheimer’s disease. Using senescence- M146L or ΔX9 PS1. Overexpression of PS1 also increased accelerated mice (SAM), Tajes and colleagues [62]showed the GSK3β-β-catenin association, thereby facilitating GSK3- that inhibition of GSK3 with lithium decreased calpain mediated phosphorylation and subsequent degradation of activation and decreased caspase-3 activity. Primary neu- β-catenin. PS1 mutants were later linked to increased ronal cultures treated with the GSK3 inhibitors lithium or GSK3 activity via decreased PI3K/Akt signaling, thereby SB415286 exhibited decreased neurite disintegration, neu- promoting decreased inhibitory serine-phosphorylation of ronal shrinkage, and nuclear condensation, further impli- GSK3 in primary neuronal cultures [49]. In cultured cating GSK3 in neurodegenerative disease progression [62]. −/− PS1 neurons the activated GSK3 was associated with In transgenic mice expressing mutant tau, chronic lithium International Journal of Alzheimer’s Disease 5 treatment reduced tau aggregation [63]. Evidence of tau- oxidative stress-induced cell death [2]. For example, Schafer related toxicity has been bolstered by studies of tau-knockout and colleagues [74] found that resistance to oxidative stress mice [64]. Mice conditionally over-expressing GSK3 and was associated with decreased GSK3 activity. Aβ treatment lacking tau performed better in the Morris water maze of cells increases oxidative stress [75, 76], as well as activates task, as compared to GSK3 over-expressing littermates [64]. GSK3, which may contribute to apoptosis. Several reports Knockout of tau reduced GSK3-mediated shrinkage of the showed that GSK3 inhibitors reduce toxicity of oxidative dentate gyrus and reduced reactive microglia, as GSK3-only stress [77, 78]. Thus, inhibition of GSK3 may be neuropro- over-expressing littermates were characterized by increased tective in Alzheimer’s disease in part by reducing oxidative brain shrinkage and increased reactive microglia compared stress-induced neurotoxicity. to control and tau-knockout mice. Neurotrophic factor deficiency has been linked with In addition to hyperphosphorylation of tau, GSK3 has neuronal loss in Alzheimer’s disease. Studies of insulin- also been linked to alternate splicing of tau, thereby possibly like growth factor-I (IGF-1) are particularly interesting promoting pro-apoptotic oligomerization and tau-induced because IGF-1 deficiency has been linked to Alzheimer’s cell death [65]. Inclusionof exon10 likely promotes disease and IGF-1-induced cellular signaling contributes to increased binding of tau and stabilization of microtubules, maintaining inhibition of GSK3 by activating the PI3K- thereby combating tau aggregate-mediated neurofibril- Akt pathway. Additionally, GSK3 inhibition has been linked lary tangle formation and neurodegeneration observed in to increases in IGF-I in the brain [79]. Bolos ´ and col- Alzheimer’s disease. Hernandez ´ and colleagues [65]exam- leagues [79] used megalin, an IGF-I receptor interacting ined the relationship between GSK3 and alternative splicing protein that is associated with transport of IGF-1, and of tau and found that in primary mouse cortical neurons found that in MDCK cells transiently transfected with or treatment with GSK3 inhibitors lithium or AR-A014418 without mini-megalin, a cDNA encoding the two peri- decreased alternative splicing of tau and promoted the membrane extracellular cysteine-rich domains, the trans- increased presence of exon 10 in tau, which promotes micro- membrane region, and the cytoplasmic region of the megalin tubule bundling and stabilization, as compared to exon 10- gene, treatment with the GSK3 inhibitor NP12 stimulated absent tau [65, 66]. Alternative splicing of tau has also been internalization of IGF-I and cell-surface megalin expression. linked to caspase-mediated cleavage and aggregation of tau Moreover, treatment of APP/PS1 transgenic mice with in Alzheimer’s disease [67]. Alternative forms of tau have NP12 significantly increased both brain and CSF IGF-I been linked to increased tau aggregation in other cells and levels. Collectively this data suggests that inhibition of cell systems [68]. over-active GSK3β that appears to occur in Alzheimer’s In contrast to reports of tau oligomerization contributing disease can promote IGF-I expression and counteract Aβ- to neurotoxicity, a few reports suggest a neuroprotec- induced toxicity. Brain-derived neurotrophic factor (BDNF) tive role for tau. Mouse neuroblastoma cells stably over- activation of TrkB receptors is also responsible for activation expressing tau were less affected by apoptotic stimuli, includ- of the PI3K/Akt pathway and inhibition of GSK3β via Ser9 ing staurosporine, camptothecin, and H O treatments, and phosphorylation [80–82]. Decreases in hippocampal and 2 2 over-expressed tau blocked GSK3 overexpression-mediated cortical BDNF levels have been reported in Alzheimer’s increases in cell death, actions that may have resulted disease [83–85], which could promote an increase in GSK3 from tau binding to GSK3 to block its induction of β- activity. Elliott and colleagues [85] showed that in neuronally catenin degradation, allowing up-regulated levels of β- differentiated P19 mouse embryonic carcinoma cells, BDNF catenin, which supports cell survival [69]. Recently, Wang altered tau phosphorylation, and that inhibition of GSK3 and colleagues [70] found that overexpression of human tau, with lithium reduced tau phosphorylation. BDNF has also in vivo in transgenic mice and in vitro in N2a cells, decreased been linked to promotion of anti-apoptotic signaling via p53 levels, decreased mitochondrial cytochrome c release, the PI3K/Akt pathway. Hetman and colleagues [86]found and decreased caspase-9 and caspase-3 activation. Treatment that trophic factor withdrawal promoted inhibition of the with lithium exaggerated the decrease in p53 expression and cell survival mediator PI3K and activated the pro-apoptotic increased pro-apoptotic processes [70]. Thus, the connec- GSK3, which was reversed by PI3K activating treatments, tions between tau and GSK3 in affecting neurodegeneration such as BDNF, by treatment with a GSK3 inhibitor, or remain to be further clarified and may be complicated by after transient transfection of a kinase-dead GSK3 mutant. employing overexpression approaches. Overexpression of wild-type or mutant β-catenin, in which all GSK3β-targeted serines were mutated to alanines, had no effect on GSK3β-mediated neuronal apoptosis [86]. 3.5. GSK3 Promotes Insults Associated with Alzheimer’s Dis- Thus, neurotrophin deficiency in Alzheimer’s disease may ease. As previously reviewed [2], GSK3 promotes apoptosis contribute to abnormally active GSK3 that can promote induced by many insults that activate the intrinsic apop- neurotoxicity. totic signaling pathway, some of which may contribute to neuronal loss in Alzheimer’s disease. For example, oxidative stress is increased in Alzheimer’s disease, as indicated by 3.6. Mechanisms by Which GSK3 May Impede Cell Survival increased markers of oxidative stress found in postmortem from Insults. GSK3 has been reported to promote apoptosis Alzheimer’s disease brain [71–73], and has been associated by regulating the actions of proteins involved in apoptosis with the loss of neuronal viability, and GSK3 promotes signaling and by regulating transcription factors known to 6 International Journal of Alzheimer’s Disease regulate the expression of apoptosis modulators. For exam- identified in Lafora Disease, an autosomal recessive form ple, GSK3 has been reported to regulate Bax, a pro-apoptotic of progressive myoclonus epilepsy that is characterized Bcl2 family member that is commonly associated with by dementia and rapid neurological deterioration [102]. the release of cytochrome c. Under apoptotic conditions, Amyotrophic lateral sclerosis has been linked to mutations Bax undergoes a conformational change associated with its in superoxide dismutase type 1 (SOD1), and expression of translocation from the cytosol to the mitochondria where mutant SOD1 in motor neurons increased GSK3 activity and it facilitates cytochrome c release in apoptotic signaling apoptosis, and GSK3 inhibitors provided protection from [87–89]. GSK3 can directly phosphorylate Bax on Ser-163, apoptosis [77]. Thus, there appear to be a variety of disease- which results in the activation of Bax [90] and inhibition of associated conditions that can cause abnormal activation of GSK3 with lithium prevented Bax activation and subsequent GSK3 that contributes to the neurodegenerative process. cytochrome c release [91]. Another Bcl2 family member, Mcl-1, an anti-apoptotic protein that can be induced after 4. GSK3 Impedes Extrinsic Apoptotic Signaling cellular stress to promote cell survival, is phosphorylated on Ser159 by GSK3 to promote Mcl1 degradation, thereby In contrast to the many studies of intrinsic apoptotic reducing the protective action of Mcl-1 [92, 93]. By these signaling mechanisms in association with loss of cell via- and other actions on the apoptotic signaling pathway, GSK3 bility in Alzheimer’s disease, few studies have addressed can reduce cellular resilience to stress and promote apoptotic the possibility that death receptor-mediated extrinsic apop- signaling. totic signaling is involved in Alzheimer’s disease. Plasma Several transcription factors that are inhibited by GSK3 membrane death receptors that can initiate apoptosis are normally promote mechanisms that promote cellular sur- members of the tumor necrosis factor (TNF) receptor vival responses to stresses that are potentially lethal insults family that contain conserved intracellular death domains, [1]. These include heat shock factor protein 1 (HSF-1), which includes Fas (CD95/Apo1), TNF-R1 (p55/CD120a), cyclic AMP response element-binding protein (CREB), and TNF-related apoptosis-inducing ligand receptor-1 (TRAIL- others, impairments of which are well-documented to R1/DR4), and TRAIL-R2 (DR5/Apo2/TRICK2/KILLER). increase the susceptibility of cells to toxic insults. HSF-1, for Studies in postmortem Alzheimer’s disease brain and par- example, promotes the expression of heat shock proteins, ticularly in Aβ-treated cells in vitro have provided some chaperones that combat cellular stress. Chu and colleagues evidence for increased death receptor-induced apoptotic [94] reported that GSK3 reduced HSF-1 activity and signaling pathway [103–111]. However, the contribution increased susceptibility to environmental stressors. Xavier of death receptor-initiated apoptosis in Alzheimer’s disease and colleagues [95] showed that overexpression of GSK3β remains to be firmly established. repressed HSF-1 transcriptional activity and DNA-binding. Although it remains unclear if death receptors contribute CREB, which can support cell survival and is activated by to cell loss in Alzheimer’s disease, we can surmise that phosphorylation at Ser133, also can be negatively regulated GSK3 is highly unlikely to contribute to this potential by GSK3 [1, 96]. Activation of CREB has been reported to neuropathological mechanism. This is because GSK3 impairs be impaired in Alzheimer’s disease hippocampal tissues [97, death receptor-induced apoptotic signaling, as opposed to its 98]. Since GSK3 inhibits CREB activity [1, 96, 99], increased promotion of intrinsic apoptotic signaling [2]. The concept GSK3 activity may contribute to the Alzheimer’s disease- that GSK3 inhibits death receptor-induced apoptosis fol- induced decrease of phospho-CREB-mediated neuroprotec- lowed the discovery that GSK3β knockout mice died during tion. Thus, by regulating these and other transcription fac- embryonic development due to massive hepatocyte apoptosis tors that influence the expression of proteins that modulate [112], which demonstrated that GSK3β is an important cellular responses to stress [1], GSK3 may contribute to inhibitor of TNFα-induced apoptosis. This inhibitory effect setting the threshold for apoptotic signaling, which may be of GSK3 on extrinsic apoptotic signaling was extended to all lowered in Alzheimer’s disease. other death receptors, as reviewed [2]. The mechanism for this action was found to be due to the presence of GSK3 in a death receptor-associated anti-apoptotic complex that 3.7. GSK3 Promotes Decreased Cell Survival in Other Neurode- impedes the initiation of apoptotic signaling [113]. Thus, generative Diseases. Many components of neurodegenerative several studies have clearly established that GSK3 is anti- processes are common among various neurodegenerative apoptotic in death receptor-mediated signaling. diseases, including apoptosis and mechanisms regulating If death receptor-induced apoptosis does contribute to apoptosis. Thus, it is not surprising that, similarly with cell loss in Alzheimer’s disease, the anti-apoptotic action of Alzheimer’s disease, GSK3 has also been linked to neuronal GSK3 in this process could very likely limit the application of death in other neurological diseases. For example, prion inhibitors of GSK3 as therapeutic agents in Alzheimer’s dis- disease shares with Alzheimer’s disease accumulations of ease because they would be able to promote extrinsic apop- protein aggregates and neuronal death [100, 101]. Mouse totic signaling. This complication was exquisitely demon- embryonic cortical neurons (E17) treated with varying strated in a study of the effects of in vivo treatment with concentrations of prion protein (PrP) peptide exhibited the GSK3 inhibitor lithium, which demonstrated increased increased GSK3 activity and increased tau phosphorylation, neuronal apoptosis mediated by lithium’s promotion of Fas- which was prevented by pretreatment with lithium. GSK3β mediated apoptotic signaling [114]. Whetherornot this activation and hyperphosphorylation of tau has also been detrimental action of GSK3 inhibitors would be deleterious International Journal of Alzheimer’s Disease 7 in Alzheimer’s disease depends on whether death receptor- [9] K. Spittaels, C. Van den Haute, J. Van Dorpe et al., “Neonatal neuronal overexpression of glycogen synthase kinase-3β induced apoptotic pathways are activated in Alzheimer’s reduces brain size in transgenic mice,” Neuroscience, vol. 113, disease, a question that remains unresolved. no. 4, pp. 797–808, 2002. [10] J. J. Lucas, F. Hernand ´ ez, P. Gome ´ z-Ramos, M. A. Moran, ´ R. 5. Conclusions Hen, and J. Avila, “Decreased nuclear β-catenin, tau hyper- phosphorylation and neurodegeneration in GSK-3β condi- GSK3 has been shown to be associated with the major tional transgenic mice,” EMBO Journal, vol. 20, no. 1-2, pp. neuropathological markers of Alzheimer’s disease and to be 27–39, 2001. abnormally activated or expressed in Alzheimer’s disease [11] F. Hernand ´ ez, J. Borrell, C. Guaza, J. Avila, and J. J. Lucas, brains, particularly in association with neuropathological “Spatial learning deficit in transgenic mice that conditionally or degenerative markers. GSK3 is activated by Aβ and over-express GSK-3β in the brain but do not form tau promotes both Aβ production and its neurotoxic actions. filaments,” Journal of Neurochemistry, vol. 83, no. 6, pp. 1529– GSK3 phosphorylates tau and may promote oligomeriza- 1533, 2002. [12] T. Engel, F. Hernand ´ ez, J. Avila, and J. J. Lucas, “Full reversal tion of tau and its aggregation, which can contribute to of Alzheimer’s disease-like phenotype in a mouse model with neurotoxicity. Apoptosis may contribute to neuronal loss in conditional overexpression of glycogen synthase kinase-3,” Alzheimer’s disease, and GSK3 promotes intrinsic apoptotic Journal of Neuroscience, vol. 26, no. 19, pp. 5083–5090, 2006. signaling induced by many insults, some of which may be [13] T. Engel, J. J. Lucas, P. Gome ´ z-Ramos, M. A. Moran, J. involved in neurodegeneration in Alzheimer’s disease. GSK3 Avila, and F. Hernandez, “Cooexpression of FTDP-17 tau and promotes intrinsic apoptotic signaling both by regulating GSK-3β in transgenic mice induce tau polymerization and signaling proteins involved in apoptosis and regulating neurodegeneration,” Neurobiology of Aging, vol. 27, no. 9, pp. transcription factors that control the expression of proteins 1258–1268, 2006. that modulate cellular responses to stress. Altogether, much [14] B. Li, J. Ryder, Y. Su et al., “Overexpression of GSK3β resulted evidence indicates that GSK3 is an integral component of the in tau hyperphosphorylation and morphology reminiscent of neurodegenerative processes in Alzheimer’s disease. pretangle-like neurons in the brain of PDGSK3β transgenic mice,” Transgenic Research, vol. 13, no. 4, pp. 385–396, 2004. [15] T. Ishizawa, N. Sahara, K. Ishiguro et al., “Co-localization of Acknowledgment glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice,” American The authors’ research was supported by grants from the Journal of Pathology, vol. 163, no. 3, pp. 1057–1067, 2003. NIMH (MH092970, MH090236, and MH038752). [16] J. Avila, E. Go´ mez De Barreda, T. Engel et al., “Tau kinase i overexpression induces dentate gyrus degeneration,” References Neurodegenerative Diseases, vol. 7, no. 1–3, pp. 13–15, 2010. [17] J. J. Pei, T. Tanaka, Y. C. Tung, E. Braak, K. Iqbal, and I. [1] C. A. Grimes and R. S. Jope, “The multifaceted roles of Grundke-Iqbal, “Distribution, levels, and activity of glycogen glycogen synthase kinase 3β in cellular signaling,” Progress in synthase kinase-3 in the Alzheimer disease brain,” Journal of Neurobiology, vol. 65, no. 4, pp. 391–426, 2001. Neuropathology and Experimental Neurology, vol. 56, no. 1, [2] E. Beurel and R. S. Jope, “The paradoxical pro- and anti- pp. 70–78, 1997. apoptotic actions of GSK3 in the intrinsic and extrinsic [18] J. J. Pei, E. Braak, H. Braak et al., “Distribution of active apoptosis signaling pathways,” Progress in Neurobiology,vol. glycogen synthase kinase 3β (GSK-3β)in brains staged 79, no. 4, pp. 173–189, 2006. for Alzheimer disease neurofibrillary changes,” Journal of [3] W. C. Earnshaw, L. M. Martins, and S. H. Kaufmann, Neuropathology and Experimental Neurology, vol. 58, no. 9, “Mammalian caspases: structure, activation, substrates, and pp. 1010–1019, 1999. functions during apoptosis,” Annual Review of Biochemistry, [19] I. Ferrer, M. Barrachina, and B. Puig, “Glycogen synthase vol. 68, pp. 383–424, 1999. kinase-3 is associated with neuronal and glial hyperphos- [4] M. O. Hengartner, “The biochemistry of apoptosis,” Nature, phorylated tau deposits in Alzheimer’s diasese, Pick’s disease, vol. 407, no. 6805, pp. 770–776, 2000. progressive supranuclear palsy and corticobasal degenera- [5] A.Ashkenazi and V.M.Dixit, “Death receptors: signaling tion,” Acta Neuropathologica, vol. 104, no. 6, pp. 583–591, and modulation,” Science, vol. 281, no. 5381, pp. 1305–1308, [20] K. Leroy, A. Boutajangout, M. Authelet, J. R. Woodgett, [6] M. Pap and G. M. Cooper, “Role of glycogen synthase kinase- B. H. Anderton, and J.-P. Brion, “The active form of 3 in the phosphatidylinositol 3- kinase/Akt cell survival glycogen synthase kinase-3β is associated with granulovac- pathway,” JournalofBiologicalChemistry, vol. 273, no. 32, pp. uolar degeneration in neurons in Alzheimers’s disease,” Acta 19929–19932, 1998. Neuropathologica, vol. 103, no. 2, pp. 91–99, 2002. [7] G. N. Bijur,P.De Sarno, and R. S. Jope,“Glycogen synthase [21] A. Takashima, K. Noguchi, K. Sato, T. Hoshino, and K. kinase-3β facilitates staurosporine- and heat shock- induced Imahori, “tau Protein kinase I is essential for amyloid β- apoptosis. Protection by lithium,” Journalof BiologicalChem- protein-induced neurotoxicity,” Proceedings of the National istry, vol. 275, no. 11, pp. 7583–7590, 2000. Academy of Sciences of the United States of America, vol. 90, [8] K. Spittaels, C. Van Den Haute, J. Van Dorpe et al., “Glycogen no. 16, pp. 7789–7793, 1993. synthase kinase-3β phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four- [22] A. Takashima, K. Noguchi, G. Michel et al., “Exposure of rat hippocampal neurons to amyloid β peptide (25-35) induces repeat tau transgenic mice,” Journal of Biological Chemistry, vol. 275, no. 52, pp. 41340–41349, 2000. the inactivation of phosphatidyl inositol-3 kinase and the 8 International Journal of Alzheimer’s Disease activation of tau protein kinase I/glycogen synthase kinase- [37] Q. L. Ma, G.P.Lim, M.E.Harris-White et al., “Antibodies 3β,” Neuroscience Letters, vol. 203, no. 1, pp. 33–36, 1996. against β-amyloid reduce Aβ oligomers, glycogen synthase [23] A. Takashima, T. Honda, K. Yasutake et al., “Activation kinase-3β activation and τ phosphorylation in vivo and in of tau protein kinase I/glycogen synthase kinase-3β by vitro,” Journal of Neuroscience Research,vol.83, no.3,pp. amyloid β peptide (25-35) enhances phosphorylation of tau 374–384, 2006. in hippocampal neurons,” Neuroscience Research, vol. 31, no. [38] W. Wei, X. Wang, and J. W. Kusiak, “Signaling events in 4, pp. 317–323, 1998. amyloid β-peptide-induced neuronal death and insulin-like [24] A. Takashima, M. Murayama, O. Murayama et al., “Presenilin growth factor I protection,” JournalofBiologicalChemistry, 1 associates with glycogen synthase kinase-3β and its sub- vol. 277, no. 20, pp. 17649–17656, 2002. strate tau,” Proceedings of the National Academy of Sciences of [39] T. Suhara, J. Magrane, K. Rosen et al., “Aβ42 generation the United States of America, vol. 95, no. 16, pp. 9637–9641, is toxic to endothelial cells and inhibits eNOS function 1998. through an Akt/GSK-3β signaling-dependent mechanism,” [25] A. Cedazo-M´ınguez, B.O. Popescu,J.M. Blanco-Millan ´ et Neurobiology of Aging, vol. 24, no. 3, pp. 437–451, 2003. al., “Apolipoprotein E and β-amyloid (1-42) regulation of [40] C. J. Phiel, C. A. Wilson, V.M.Y. Lee, and P.S.Klein,“GSK- glycogen synthase kinase-3β,” Journal of Neurochemistry,vol. 3α regulates production of Alzheimer’s disease amyloid-β 87, no. 5, pp. 1152–1164, 2003. peptides,” Nature, vol. 423, no. 6938, pp. 435–439, 2003. [26] A. R. Alvarez, J. A. Godoy, K. Mullendorff,G.H.Olivares, [41] X. Sun, S. Sato, O. Murayama et al., “Lithium inhibits M. Bronfman, and N. C. Inestrosa, “Wnt-3a overcomes β- amyloid secretion in COS7 cells transfected with amyloid amyloid toxicity in rat hippocampal neurons,” Experimental precursor protein C100,” Neuroscience Letters, vol. 321, no. Cell Research, vol. 297, no. 1, pp. 186–196, 2004. 1-2, pp. 61–64, 2002. [27] S. Hu, A.N. Begum,M.R. Jones et al., “GSK3inhibitors [42] Y. Su,J.Ryder, B.Liet al., “Lithium, acommon drug for show benefits inanAlzheimer’s disease (AD) model of bipolar disorder treatment, regulates amyloid-β precursor neurodegeneration but adverse effects in control animals,” protein processing,” Biochemistry, vol. 43, no. 22, pp. 6899– Neurobiology of Disease, vol. 33, no. 2, pp. 193–206, 2009. 6908, 2004. [28] S. H. Koh, M. Y. Noh, and S.H.Kim,“Amyloid-beta-induced [43] F. Kirschenbaum, S. C. Hsu,B.Cordell, and J. V.McCarthy, neurotoxicity is reduced by inhibition of glycogen synthase “Glycogen synthase kinase-3β regulates presenilin 1 C- kinase-3,” Brain Research, vol. 1188, no. 1, pp. 254–262, 2008. terminal fragment levels,” Journalof BiologicalChemistry,vol. [29] G. Alvarez, J. R. Munoz- ˜ Montano ˜ , J. Satru´ stegui, J. Avila, E. 276, no. 33, pp. 30701–30707, 2001. Bogone ´ z, and J. D´ıaz-Nido, “Lithium protects cultured neu- [44] A. E. Aplin, J. S. Jacobsen, B. H. Anderton, and J. M. rons against β-amyloid-induced neurodegeneration,” FEBS Gallo, “Effect of increased glycogen synthase kinase-3 activity Letters, vol. 453, no. 3, pp. 260–264, 1999. upon the maturation of the amyloid precursor protein in [30] A. Ferreira, Q. Lu, L. Orecchio, and K. S. Kosik, “Selective transfected cells,” NeuroReport, vol. 8, no. 3, pp. 639–643, phosphorylation of adult tau isoforms in mature hippocam- 1997. pal neurons exposed to fibrillar aβ,” Molecular and Cellular [45] Z. Zhang, H. Hartmann, V. M. Do et al., “Destabilization of Neurosciences, vol. 9, no. 3, pp. 220–234, 1997. β-catenin by mutations in presenilin-1 potentiates neuronal [31] A. Takashima, H. Yamaguchi, K. Noguchi et al., “Amyloid, apoptosis,” Nature, vol. 395, no. 6703, pp. 698–702, 1998. β peptide induces cytoplasmic accumulation of amyloid [46] C. C. Weihl, G. D. Ghadge, S.G.Kennedy, N. Hay,R. J. Miller, protein precursor via tau protein kinase I/glycogen synthase and R. P. Roos, “Mutant presenilin-1 induces apoptosis and kinase-3β in rat hippocampal neurons,” Neuroscience Letters, downregulates Akt/PKB,” Journal of Neuroscience,vol.19, no. vol. 198, no. 2, pp. 83–86, 1995. 13, pp. 5360–5369, 1999. [32] H. Wei, P. R. Leeds, Y. Qian,W.Wei,R. W.Chen, and DE. [47] C. Twomey and J. V. McCarthy, “Presenilin-1 is an unprimed M. Chuang, “β-amyloid peptide-induced death of PC 12 cells glycogen synthase kinase-3β substrate,” FEBS Letters,vol. and cerebellar granule cell neurons is inhibited by long-term 580, no. 17, pp. 4015–4020, 2006. lithium treatment,” European Journal of Pharmacology,vol. [48] D. E. Kang,S.Soriano, M. P.Frosch et al.,“Presenilin 1 392, no. 3, pp. 117–123, 2000. facilitates the constitutive turnover of β-catenin: differential [33] N. C. Inestrosa, G. V. De Ferrari, J. L. Garrido et al., “Wnt activity of Alzheimer’s disease-linked PS1 mutants in the β- signaling involvement in β-amyloid-dependent neurodegen- catenin-signaling pathway,” Journal of Neuroscience, vol. 19, eration,” Neurochemistry International,vol.41, no.5,pp. no. 11, pp. 4229–4237, 1999. 341–344, 2002. [49] L. Baki, R. L. Neve, Z. Shao,J.Shioi,A. Georgakopoulos, and [34] W. Noble, E. Planel, C. Zehr et al., “Inhibition of glycogen N. K. Robakis, “Wild-type but not FAD mutant presenilin- synthase kinase-3 by lithium correlates with reduced tauopa- 1 prevents neuronal degeneration by promoting phos- thy and degeneration in vivo,” Proceedings of the National phatidylinositol 3-kinase neuroprotective signaling,” Journal Academy of Sciences of the United States of America, vol. 102, of Neuroscience, vol. 28, no. 2, pp. 483–490, 2008. no. 19, pp. 6990–6995, 2005. [50] J. B. J. Kwok, C.T.Loy,G.Hamilton etal.,“Glycogen synthase [35] L. Sereno´, M. Coma,M.Rodr´ıguez et al., “A novel GSK- kinase-3β and tau genes interact in Alzheimer’s disease,” 3β inhibitor reduces Alzheimer’s pathology and rescues Annals of Neurology, vol. 64, no. 4, pp. 446–454, 2008. neuronal loss in vivo,” Neurobiology of Disease, vol. 35, no. [51] G. V. De Ferrari, M. A. Chacon, M. I. Barria et al., “Activation 3, pp. 359–367, 2009. of Wnt signaling rescues neurodegeneration and behavioral [36] E. Rockenstein, M. Torrance, A. Adame et al., “Neuroprotec- impairments induced by β-amyloid fibrils,” Molecular Psychi- tive effects of regulators of the glycogen synthase kinase-3β atry, vol. 8, no. 2, pp. 195–208, 2003. signaling pathway in a transgenic model of Alzheimer’s dis- [52] R. A. Fuentealba, G. Farias, J. Scheu, M. Bronfman, M. P. ease are associated with reduced amyloid precursor protein Marzolo, and N. C. Inestrosa, “Signal transduction during phosphorylation,” Journal of Neuroscience,vol. 27, no.8,pp. amyloid-β-peptide neurotoxicity: role in Alzheimer disease,” 1981–1991, 2007. Brain Research Reviews, vol. 47, no. 1–3, pp. 275–289, 2004. International Journal of Alzheimer’s Disease 9 [53] W. Cerpa, E. M. Toledo, L. Varela-Nallar, and N. C. Inestrosa, involved in Alzheimer’s nerodegeneration,” Proceedings of the “The role of WNT signaling in neuroprotection,” Drug News National Academy of Sciences of the United States of America, and Perspectives, vol. 22, no. 10, pp. 579–591, 2009. vol. 104, no. 9, pp. 3591–3596, 2007. [54] P. J. Dolan and G. V. W. Johnson, “The role of tau kinases in [70] H.-H. Wang, H.-L. Li, R. Liu et al., “Tau overexpression Alzheimer’s disease,” Current Opinion in Drug Discovery and inhibits cell apoptosis with the mechanisms involving mul- Development, vol. 13, no. 5, pp. 595–603, 2010. tiple viability-related factors,” Journal of Alzheimer’s Disease, [55] K. Ishiguro, A. Omori, M. Takamatsu et al., “Phosphoryla- vol. 21, no. 1, pp. 167–179, 2010. tion sites on tau by tau protein kinase I, a bovine derived [71] M. A. Pappolla,Y.J.Chyan,R. A.Omar et al., “Evidence kinase generating an epitope of paired helical filaments,” of oxidative stress and in vivo neurotoxicity of β-amyloid in Neuroscience Letters, vol. 148, no. 1-2, pp. 202–206, 1992. a transgenic mouse model of Alzheimer’s disease: a chronic [56] M. Hong, D. C.R. Chen, P. S. Klein, and V.M.Y.Lee, oxidative paradigm for testing antioxidant therapies in vivo,” “Lithium reduces tau phosphorylation by inhibition of American Journal of Pathology, vol. 152, no. 4, pp. 871–877, glycogen synthase kinase-3,” Journal of Biological Chemistry, 1998. vol. 272, no. 40, pp. 25326–25332, 1997. [72] D. Galasko and T. J. Montine, “Biomarkers of oxidative dam- [57] J. Avila, J. J. Lucas, M. Per ´ ez, and F. Hernand ´ ez, “Role of tau age and inflammation in Alzheimers disease,” Biomarkers in protein in both physiological and pathological conditions,” Medicine, vol. 4, no. 1, pp. 27–36, 2010. Physiological Reviews, vol. 84, no. 2, pp. 361–384, 2004. [73] M. Padurariu, A. Ciobica, L. Hritcu, B. Stoica, W. Bild, and [58] K. Santacruz, J. Lewis, T. Spires et al., “Medicine: tau C. Stefanescu, “Changes of some oxidative stress markers in suppression in a neurodegenerative mouse model improves the serum of patients with mild cognitive impairment and memory function,” Science, vol. 309, no. 5733, pp. 476–481, Alzheimer’s disease,” Neuroscience Letters, vol. 469, no. 1, pp. 2005. 6–10, 2010. [59] K. Imahori and T. Uchida, “Physiology and pathology of tau [74] M. Schaf ¨ er, S. Goodenough, B. Moosmann, and C. Behl, protein kinases in relation to Alzheimer’s disease,” Journal of “Inhibition of glycogen synthase kinase 3β is involved in the Biochemistry, vol. 121, no. 2, pp. 179–188, 1997. resistance to oxidative stress in neuronal HT22 cells,” Brain [60] N. Sahara, M. Murayama, B. Lee et al., “Active c-jun Research, vol. 1005, no. 1-2, pp. 84–89, 2004. N-terminal kinase induces caspase cleavage of tau and [75] L. Wan, G. Nie, J. Zhang et al., “β-amyloid peptide increases additional phosphorylation by GSK-3β is required for tau levels of iron content and oxidative stress in human cell and aggregation,” European Journal of Neuroscience, vol. 27, no. Caenorhabditis elegans models of Alzheimer disease,” Free 11, pp. 2897–2906, 2008. Radical Biology and Medicine, vol. 50, no. 1, pp. 122–129, [61] M. Goedert, M. G. Spillantini, R. Jakes, D. Rutherford, and 2011. R. A. Crowther, “Multiple isoforms of human microtubule- [76] H. M. Abdul, V. Calabrese, M. Calvani, and D. A. Butterfield, associated protein tau: sequences and localization in neu- “Acetyl-L-carnitine-induced up-regulation of heat shock rofibrillary tangles of Alzheimer’s disease,” Neuron,vol. 3,no. proteins protects cortical neurons against amyloid-beta 4, pp. 519–526, 1989. peptide 1-42-mediated oxidative stress and neurotoxicity: [62] M. Tajes, J. Gutierrez-Cuesta, J. Folch et al., “Lithium treat- implications for Alzheimer’s disease,” Journal of Neuroscience ment decreases activities of tau kinases in a murine model Research, vol. 84, no. 2, pp. 398–408, 2006. of senescence,” Journal of Neuropathology and Experimental [77] S. H. Koh, Y. B. Lee, K. S. Kim et al., “Role of GSK-3β Neurology, vol. 67, no. 6, pp. 612–623, 2008. activity in motor neuronal cell death induced by G93A or [63] M. Per ´ ez, F. Hernand ´ ez, F. Lim, J. D´ıaz-Nido, and J. A4V mutant hSOD1 gene,” European Journal of Neuroscience, Avila, “Chronic lithium treatment decreases mutant tau vol. 22, no. 2, pp. 301–309, 2005. protein aggregation in a transgenic mouse model,” Journal [78] Y. J. Zhang, Y. F. Xu, Y. H.Liu,J.Yin,and J. Z. Wang, of Alzheimer’s Disease, vol. 5, no. 4, pp. 301–308, 2003. “Nitric oxide induces tau hyperphosphorylation via glycogen [64] E. G. de Barreda, M. Pe´rez,P.G.Ramos et al., “Tau- synthase kinase-3β activation,” FEBS Letters, vol. 579, no. 27, knockout mice show reduced GSK3-induced hippocampal pp. 6230–6236, 2005. degeneration and learning deficits,” Neurobiology of Disease, [79] M. Bolos, ´ S. Fernandez, and I. Torres-Aleman, “Oral admin- vol. 37, no. 3, pp. 622–629, 2010. istration of a GSK3 inhibitor increases brain insulin-like [65] F. Hernand ´ ez, M. Pe´rez, J. J. Lucas, A. M. Mata, R. Bhat, and growth factor I levels,” Journal of Biological Chemistry,vol. J. Avila, “Glycogen synthase kinase-3 plays a crucial role in 285, no. 23, pp. 17693–17700, 2010. tau exon 10 splicing and intranuclear distribution of SC35: [80] A. Patapoutian and L. F. Reichardt, “Trk receptors: mediators implications for Alzheimer’s disease,” Journal of Biological of neurotrophin action,” Current Opinion in Neurobiology, Chemistry, vol. 279, no. 5, pp. 3801–3806, 2004. vol. 11, no. 3, pp. 272–280, 2001. [66] G. Lee and S. L. Rook, “Expression of tau protein in [81] G. Gallo, A.F. Ernst,S. C.McLoon, and P. C. Letourneau, non-neuronal cells: microtubule binding and stabilization,” “Transient PKA activity is required for initiation but not JournalofCellScience, vol. 102, no. 2, pp. 227–237, 1992. maintenance of BDNF-mediated protection from nitric [67] J. H. Cho and G. V. W. Johnson, “Glycogen synthase kinase oxide-induced growth-cone collapse,” Journal of Neuro- 3β induces caspase-cleaved tau aggregation in situ,” Journal of science, vol. 22, no. 12, pp. 5016–5023, 2002. Biological Chemistry, vol. 279, no. 52, pp. 54716–54723, 2004. [82] L. Mai, R. S. Jope, and X. Li, “BDNF-mediated signal [68] A. Go´mez-Ramos,X.Abad, M. L. Fanarraga,R. Bhat, J. C. transduction is modulated by GSK3β and mood stabilizing Zabala, and J. Avila, “Expression of an altered form of tau in agents,” Journal of Neurochemistry, vol. 82, no. 1, pp. 75–83, Sf9 insect cells results in the assembly of polymers resembling 2002. Alzheimer’s paired helical filaments,” Brain Research,vol. [83] H. S. Phillips, J. M. Hains, M. Armanini, G. R. Laramee, S. 1007, no. 1-2, pp. 57–64, 2004. A. Johnson, and J. W. Winslow, “BDNF mRNA is decreased [69] H. L. Li, H. H. Wang, S. J. Liu et al., “Phosphorylation of tau in the hippocampus of individuals with Alzheimer’s disease,” antagonizes apoptosis by stabilizing β-catenin, a mechanism Neuron, vol. 7, no. 5, pp. 695–702, 1991. 10 International Journal of Alzheimer’s Disease [84] M. G. Murer, Q. Yan, and R. Raisman-Vozari, “Brain-derived element binding protein in the hippocampus of dementia of neurotrophic factor in the control human brain, and in the Alzheimer type,” Brain Research, vol. 824, no. 2, pp. 300– Alzheimer’s disease and Parkinson’s disease,” Progress in 303, 1999. Neurobiology, vol. 63, no. 1, pp. 71–124, 2001. [99] F. Gotsc ¨ hel, C. Kern, S. Lang et al., “Inhibition of GSK3 [85] E. Elliott, R. Atlas, A. Lange, and I. Ginzburg, “Brain-derived differentially modulates NF-κB, CREB, AP-1 and β-catenin neurotrophic factor induces a rapid dephosphorylation of signaling in hepatocytes, but fails to promote TNF-α-induced tau protein through a PI-3Kinase signalling mechanism,” apoptosis,” Experimental Cell Research, vol. 314, no. 6, pp. European Journal of Neuroscience, vol. 22, no. 5, pp. 1081– 1351–1366, 2008. 1089, 2005. [100] M. Per ´ ez, A. I. Rojo, F. Wandosell, J. D´ıaz-Nido, and J. [86] M. Hetman, J. E. Cavanaugh, D. Kimelman, and X. Zhengui, Avila, “Prion peptide induces neuronal cell death through a “Role of glycogen synthase kinase-3β in neuronal apoptosis pathway involving glycogen synthase kinase 3,” Biochemical induced by trophic withdrawal,” Journal of Neuroscience,vol. Journal, vol. 372, no. 1, pp. 129–136, 2003. 20, no. 7, pp. 2567–2574, 2000. [101] NIH/National Institute of Allergy and Infectious Diseases, [87] K. G. Wolter, YI. T. Hsu, C. L. Smith, A. Nechushtan, XU. G. “New form of prion disease damages brain arteries,” Sci- Xi, and R. J. Youle, “Movement of Bax from the cytosol to enceDaily, 2010. mitochondria during apoptosis,” Journalof CellBiology,vol. [102] R. Puri, T. Suzuki, K. Yamakawa, and S. Ganesh, “Hyperphos- 139, no. 5, pp. 1281–1292, 1997. phorylation and aggregation of Tau in laforin-deficient mice, [88] YI.T. Hsu,K. G.Wolter, and R.J. Youle,“Cytosol-to- an animal model for lafora disease,” Journal of Biological membrane redistribution of Bax and Bcl-X during apopto- Chemistry, vol. 284, no. 34, pp. 22657–22663, 2009. sis,” Proceedings of the National Academy of Sciences of the [103] S. M. De La Monte, Y. K. Sohn, and J. R. Wands, “Correlates United States of America, vol. 94, no. 8, pp. 3668–3672, 1997. of p53- and Fas (CD95)-mediated apoptosis in Alzheimer’s [89] M. Saito, S. J. Korsmeyer, and P. H. Schlesinger, “BAX- disease,” Journal of the Neurological Sciences, vol. 152, no. 1, dependent transport of cytochrome C reconstituted in pure pp. 73–83, 1997. liposomes,” Nature Cell Biology, vol. 2, no. 8, pp. 553–555, [104] K. J. Ivins, P. L. Thornton, T. T. Rohn, and C. W. Cotman, “Neuronal apoptosis induced by β-amyloid is mediated by [90] D. A. Linseman, B.D.Butts, T.A.Precht etal., “Glyco- caspase-8,” Neurobiology of Disease, vol. 6, no. 5, pp. 440–449, gen synthase kinase-3β phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis,” Journal of Neuroscience, vol. 24, no. 44, pp. 9993–10002, 2004. [105] I. Ferrer, B. Puig, J. Krupinski, M. Carmona, and R. Blanco, “Fas and Fas ligand expression in Alzheimer’s disease,” Acta [91] T. C. P. Somervaille, D. C. Linch, and A. Khwaja, “Growth factor withdrawal from primary human erythroid progeni- Neuropathologica, vol. 102, no. 2, pp. 121–131, 2001. tors induces apoptosis through a pathway involving glycogen [106] Y. Morishima, Y. Gotoh, J. Zieg et al., “β-amyloid induces synthase kinase-3 and Bax,” Blood, vol. 98, no. 5, pp. 1374– neuronal apoptosis via a mechanism that involves the c-Jun 1381, 2001. N-terminal kinase pathway and the induction of fas ligand,” [92] U. Maurer,C.Charvet, A.S. Wagman, E. Dejardin, and D. R. Journal of Neuroscience, vol. 21, no. 19, pp. 7551–7560, 2001. Green, “Glycogen synthase kinase-3 regulates mitochondrial [107] G. Cantarella, D. Uberti, T. Carsana, G. Lombardo, R. outer membrane permeabilization and apoptosis by destabi- Bernardini, and M. Memo, “Neutralization of TRAIL death lization of MCL-1,” Molecular Cell, vol. 21, no. 6, pp. 749– pathway protects human neuronal cell line from β-amyloid 760, 2006. toxicity,” Cell Death and Differentiation, vol. 10, no. 1, pp. [93] Q. Ding,X.He, J. M. Hsu etal., “Degradationof Mcl-1 by 134–141, 2003. β-TrCP mediates glycogen synthase kinase 3-induced tumor [108] J. H. Su, A. J. Anderson, D. H. Cribbs et al., “Fas and Fas suppression and chemosensitization,” Molecular and Cellular Ligand are associated with neuritic degeneration in the AD Biology, vol. 27, no. 11, pp. 4006–4017, 2007. brain and participate in β-amyloid-induced neuronal death,” [94] B. Chu, R. Zhong, F. Soncin, M. A. Stevenson, and S. K. Neurobiology of Disease, vol. 12, no. 3, pp. 182–193, 2003. Calderwood, “Transcriptional activity of heat shock factor 1 [109] D. T. Yew, W. Ping Li, and W. K. Liu, “Fas and activated at 37 c is repressed through phosphorylation on two distinct caspase 8 in normal, Alzheimer and multiple infarct brains,” serine residues by glycogen synthase kinase 3α and protein Neuroscience Letters, vol. 367, no. 1, pp. 113–117, 2004. kinases cα and cζ,” Journalof BiologicalChemistry, vol. 273, [110] C. K. Wu, L. Thal, D. Pizzo, L. Hansen, E. Masliah, and no. 29, pp. 18640–18646, 1998. C. Geula, “Apoptotic signals within the basal forebrain [95] I. J. Xavier, P. A. Mercier, C. M. McLoughlin, A. Ali, J. R. cholinergic neurons in Alzheimer’s disease,” Experimental Woodgett, and N. Ovsenek, “Glycogen synthase kinase 3β Neurology, vol. 195, no. 2, pp. 484–496, 2005. negatively regulates both DNA-binding and transcriptional [111] D. Uberti, G. Ferrari-Toninelli, S. A. Bonini et al., “Blockade activities of heat shock factor 1,” Journal of Biological of the tumor necrosis factor-related apoptosis inducing lig- Chemistry, vol. 275, no. 37, pp. 29147–29152, 2000. and death receptor DR5 prevents β-amyloid neurotoxicity,” [96] J. W. Tullai, J. Chen, M. E. Schaffer, E. Kamenetsky, S. Kasif, Neuropsychopharmacology, vol. 32, no. 4, pp. 872–880, 2007. and G. M. Cooper, “Glycogen synthase kinase-3 represses [112] K. P. Hoeflich, J. Luo, E. A. Rubie, M. S. Tsao, OU. Jin, and J. cyclic AMP Response element-binding protein (CREB)- R. Woodgett, “Requirement for glycogen synthase kinase-3β targeted Immediate early genes in quiescent cells,” Journal of in cell survival and NF-κBactivation,” Nature, vol. 406, no. Biological Chemistry, vol. 282, no. 13, pp. 9482–9491, 2007. 6791, pp. 86–90, 2000. [97] A. J. Silva, J. H. Kogan, P. W. Frankland, and S. Kida, “CREB and memory,” Annual Review of Neuroscience,vol.21, pp. [113] M. Sun, L. Song, Y. Li, T. Zhou, and R. S. Jope, “Identification 127–148, 1998. of an antiapoptotic protein complex at death receptors,” Cell [98] M. Yamamoto-Sasaki, H. Ozawa, T. Saito, M. Rosle ¨ r, and P. Death and Differentiation, vol. 15, no. 12, pp. 1887–1900, Riederer, “Impaired phosphorylation of cyclic AMP response 2008. International Journal of Alzheimer’s Disease 11 ´ ´ [114] R. Gomez-Sintes, F. Hernandez, A. Bortolozzi et al., “Neu- ronal apoptosis and reversible motor deficit in dominant- negative GSK-3 conditional transgenic mice,” EMBO Journal, vol. 26, no. 11, pp. 2743–2754, 2007. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Alzheimer's Disease Hindawi Publishing Corporation

Regulation of Cell Survival Mechanisms in Alzheimer's Disease by Glycogen Synthase Kinase-3

Loading next page...
 
/lp/hindawi-publishing-corporation/regulation-of-cell-survival-mechanisms-in-alzheimer-s-disease-by-FTB6N5CWID

References (117)

Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2011 Marjelo A. Mines et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
2090-8024
DOI
10.4061/2011/861072
Publisher site
See Article on Publisher Site

Abstract

SAGE-Hindawi Access to Research International Journal of Alzheimer’s Disease Volume 2011, Article ID 861072, 11 pages doi:10.4061/2011/861072 Review Article Regulation of Cell Survival Mechanisms in Alzheimer’s Disease by Glycogen Synthase Kinase-3 Marjelo A. Mines, Eleonore Beurel, and Richard S. Jope Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Sparks Center 1057, 1720 Seventh Avenue South, Birmingham, AL 35294-0017, USA Correspondence should be addressed to Richard S. Jope, jope@uab.edu Received 15 January 2011; Accepted 9 March 2011 Academic Editor: Adam Cole Copyright © 2011 Marjelo A. Mines et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A pivotal role has emerged for glycogen synthase kinase-3 (GSK3) as an important contributor to Alzheimer’s disease pathology. Evidence for the involvement of GSK3 in Alzheimer’s disease pathology and neuronal loss comes from studies of GSK3 overexpression, GSK3 localization studies, multiple relationships between GSK3 and amyloid β-peptide (Aβ), interactions between GSK3 and the microtubule-associated tau protein, and GSK3-mediated apoptotic cell death. Apoptotic signaling proceeds by either an intrinsic pathway or an extrinsic pathway. GSK3 is well established to promote intrinsic apoptotic signaling induced by many insults, several of which may contribute to neuronal loss in Alzheimer’s disease. Particularly important is evidence that GSK3 promotes intrinsic apoptotic signaling induced by Aβ. GSK3 appears to promote intrinsic apoptotic signaling by modulating proteins in the apoptosis signaling pathway and by modulating transcription factors that regulate the expression of proteins involved in apoptosis. Thus, GSK3 appears to contribute to several neuropathological mechanisms in Alzheimer’s disease, including apoptosis-mediated neuronal loss. 1. Introduction 2. Overview of Cell Death in Alzheimer’s Disease Ten years ago we first noted that glycogen synthase kinase-3 (GSK3) appeared to be linked to all of the major pathological Among the known mechanisms that may contribute to mechanisms that had been identified in Alzheimer’s disease loss of neurons in Alzheimer’s disease brain, apoptosis has [1]. Since then, a remarkable amount of new evidence has received the most attention. Apoptotic signaling is generally solidified the central role of GSK3 in Alzheimer’s disease neu- classified as proceeding by either an intrinsic pathway or an ropathology, as exemplified by this entire issue being devoted extrinsic pathway. Of these, the intrinsic apoptotic signaling to the subject. Among the early identified links between pathway has predominated in studies of Alzheimer’s disease. GSK3 and Alzheimer’s disease was the discovery that GSK3 Intrinsic apoptotic signaling is most often induced by promotes the intrinsic apoptotic signaling pathway that may intracellular damage that leads to mitochondrial release of be partly responsible for neuronal loss in Alzheimer’s disease cytochrome c and the activation of intracellular cysteine [2]. Here we review the multiple cellular pathways influenced proteases called caspases [3], particularly caspase-9 and by GSK3 that may contribute to changes in cell viability in caspase-3, with a variety of other pro-apoptotic media- Alzheimer’s disease. tors and caspases contributing to the eventual outcome 2 International Journal of Alzheimer’s Disease of apoptosis [4]. Extrinsic apoptotic signaling is initiated greatly increased by modestly elevated levels of GSK3β, by stimulation of plasma membrane death receptors that demonstrating that increased GSK3 activity promotes apop- initiate apoptosis by activation of caspase-8, and subsequent totic signaling induced by a variety of toxic agents [7]. These apoptotic signaling can proceed through the mitochondrial and other in vitro studies demonstrating that increased GSK3 pathway or independently of mitochondria by caspase-8- activity can promote activation of the intrinsic apoptotic mediated direct activation of caspase-3 [5]. Of these two signaling pathway and that inhibition of GSK3 provides apoptotic signaling pathways, the intrinsic system has been protection from apoptosis have been previously reviewed in the focus of the great majority of studies of apoptotic cell detail [1, 2]. death mechanisms in Alzheimer’s disease. The results of in vitro studies that showed promotion of intrinsic apoptotic signaling by GSK3 raised the question of whether abnormal increases in GSK3 in vivo may contribute 3. GSK3 Promotes Intrinsic Apoptotic Signaling to neuronal death in neurodegenerative diseases, such as Alzheimer’s disease. One approach to test this that has Much evidence indicates that promotion of the intrinsic been productive is to study transgenic mice over-expressing apoptotic signaling pathway by GSK3 may be particularly GSK3. Spittaels and colleagues [8] studied transgenic mice important in the apoptosis and neuronal loss that occurs in over-expressing constitutively active S9A-GSK3β and found Alzheimer’s disease. This is because GSK3 has been shown hyperphosphorylation of the microtubule-associated protein to promote apoptosis following a wide range of insults tau and altered behaviors in sensorimotor tasks in these that activate the intrinsic apoptotic signaling pathway [2]. mice. Mice postnataly over-expressing S9A-GSK3β driven by In order to promote intrinsic apoptotic signaling, GSK3 the thy-1 promoter in neurons exhibited decreased brain must be active. The major mechanism regulating GSK3 volume and cell size, increased neuronal densities, and activity is phosphorylation of an N-terminal serine in learning deficits in the Morris water maze [9]. Lucas and col- each of the two paralogs (commonly called isoforms) of leagues [10] created transgenic mice over-expressing GSK3β GSK3, serine9-GSK3β or serine21-GSK3α. Phosphorylation in regions specifically relevant to Alzheimer’s disease, the of these regulatory serines inhibits GSK3, thus signaling hippocampus and neuronal layers I–VI of the cortex. These activities that reduce GSK3 serine-phosphorylation activate mice displayed evidence of apoptosis activation, including GSK3. The inhibitory serines in GSK3 can be phosphorylated increased TUNEL staining and caspase-3 activation in the by several different kinases. The most often studied of these dentate gyrus [10]. Concomitant with increased markers is Akt (also called protein kinase B), which itself is activated of apoptosis, the GSK3β-over-expressing mice exhibited by multiple receptor-coupled signaling pathways that signal activated astrocytes and microglia. These mice also displayed through phosphatidylinositol 3-kinase (PI3K), such as sig- deficits in learning in the Morris water maze, but tau naling induced by a variety of neurotrophin receptors. Thus, filaments were concluded to not be involved in the learning one mechanism by which GSK3 can be activated is by signals deficits [11]. Further studies of these mice took advan- that reduce its serine-phosphorylation mediated by Akt or tage of the capability of terminating GSK3β overexpression other kinases. A widely used method to study the actions with doxycyclin treatment, which reduced GSK3β levels, of GSK3β is to express GSK3β with a serine9-to-alanine9 reduced tau phosphorylation, increased microtubule poly- mutation (S9A-GSK3β) to maintain expressed GSK3β fully merization, reduced reactive astrocytosis, restored spatial active. GSK3 also must be phosphorylated on a tyrosine memory, and decreased levels of active caspase-3 [12]. When residue for full activity, tyrosine216-GSK3β or tyrosine279- the tetracycline-regulated conditional transgenic mice were GSK3α. Although the mechanisms regulating tyrosine- crossed with mice over-expressing tau carrying a FTDP-17 phosphorylation of GSK3 are still not well-understood, a mutation, GSK3-mediated hyperphosphorylated tau had an number of reports have indicated that GSK3 activity can be increased propensity to form filaments, leading to neurofib- increased by signals that increase tyrosine-phosphorylated rillary tangles (NFTs), and displayed microencephaly at 18 GSK3. months of age [13]. Expression of constitutively active S9A- GSKβ in the cortex and hippocampus caused hyperphos- 3.1. Overexpression of GSK3 Is Sufficient to Activate Apoptosis. phorylated tau, neurofibrillary tangles, and morphological changes in neuronal structure [14]. Mice expressing human Overexpression of GSK3 in cells or rodent brains has been shown to induce apoptosis and neuronal death in many P301L tau (JNLP3 mice), expressing mutant amyloid pre- reports. The first study of this type showed that that transient cursor protein (Tg2576 mice), and expressing both P301L tau mutationand mutant APPprotein (TAPPmice),all overexpression of wild-type GSK3β was sufficient to induce apoptosis in cultured PC12 cells [6]. Furthermore, this report displayed increased tyrosine-phosphorylated GSK3α/β in showed that expression of a dominant-negative kinase-dead spinal cord and amygdala neurons characterized by gran- mutant of GSK3β was sufficient to reduce apoptosis that ulovacular degenerative granules and neurofibrillary tangles was induced by inhibition of PI3K, demonstrating that in the JNPL3 and TAPP mice [15]. Avila and colleagues [16] reported that mice over-expressing GSK3β had a 2-fold GSK3 is a major mediator of apoptosis in conditions of reduced PI3K activity [6]. Bijur and colleagues [7]extended increase in tau levels and a decrease in dentate gyrus volume, those findings to show that although relatively low levels of and suggested that increased GSK3β activity, particularly in the dentate gyrus, hinders neurogenesis, thereby promoting over-expressed GSK3β did not induce apoptosis in human neuroblastoma SH-SY5Y cells, pro-apoptotic signaling was the decreased tissue volume. Collectively, these findings in International Journal of Alzheimer’s Disease 3 transgenic mice indicate that GSK3 promotes pathological tissues. Increases in GSK3 immunoreactivity co-localized process associated with Alzheimer’s disease, but whether specifically with granulovacular degenerative granules, and GSK3 promoted decreases in neuronal viability often was there were no detectable changes in GSK3 immunoreactivity not directly investigated due to the difficulty in capturing within neurofibrillary tangles. Ferrer and colleagues [19]also transient markers of apoptosis in in vivo studies. reported increased GSK3 immunoreactivity in granulovacu- lar degenerative bodies located in neuronal cell bodies, and also found increased GSK3 immunoreactivity in glial cells in 3.2. Localization of GSK3 in Alzheimer’s Disease Brain. postmortem human brain tissues. Localization studies in postmortem Alzheimer’s disease brain have been used to determine if GSK3 is accumulated or activated in areas with prominent neurodegeneration. Pei 3.3. Toxicity Associated with Amyloid-β Peptide (Aβ). Sub- and colleagues [17] reported increased GSK3α and GSK3β stantial evidence has demonstrated that Aβ activates GSK3 immunoreactivities in plaques and CA1 hippocampal neu- by decreasing its inhibitory serine-phosphorylation, which rons, and co-staining with Congo red indicated that many appears to contribute to Aβ-induced increased tau phos- cells with increased GSK3β immunoreactivity contained phorylation and to Aβ-induced neurotoxicity [21–30]. These hyperphosphorylated tau and neurofibrillary tangles. Sub- studies showing Aβ-induced activation of GSK3 have used sequently, Pei and colleagues [18] compared non-diseased a variety of peptides, including Aβ ,Aβ ,and the 1–40 1–42 brains, deemed Stage 0 cases, to Alzheimer’s disease-like 25–35 peptide fragment, indicating that accumulation of brains from middle-aged and senescent patients, classified as any of these may activate GSK3, although perhaps by stages A–C according to the extent of amyloid deposition, utilizing different signaling mechanisms, which remain to and NF I–VI according to the extent of neurofibrillary be identified. Takashima and colleagues [21–24, 31]first tangle pathology. They found only moderate active GSK3β identified a neuroprotective effect of inhibiting GSK3 (at that staining in normal brains (Stage 0) in neurons of the time also called tau protein kinase-1) against Aβ-induced entorhinal cortex and CA1 and CA2 regions of the hip- toxicity. They found that in cultured rat hippocampal pocampus [18]. Inactive GSK3β staining was pronounced neurons Aβ treatment increased GSK3β activity and pre- in entorhinal cortical neurons and the hippocampal CA1 treatment with GSK3β antisense oligonucleotides prevented region relative to staining for active GSK3. Stage 0/NF I-II Aβ-induced cell death and reduced tau phosphorylation. brains also had increased inactive GSK3β, relative to active These studies indicated that GSK3 is involved in Aβ-induced GSK3, immunoreactivity in the entorhinal cortex and hip- tau phosphorylation and neurotoxicity. Subsequent reports pocampal CA1 region. Stage III/IV brains showed increased also demonstrated that inhibitors of GSK3, such as lithium tau phosphorylation immunoreactivity (AT8 antibody) and or SB216763, reduced Aβ-induced tau phosphorylation and tangle formation in the entorhinal cortex and hippocam- cell death in cultured neurons [27, 29, 32]. Inestrosa and pal CA1 region, and tangle-containing neurons also had colleagues [33] found that treatment with lithium pre- increased active, as well as inactive, GSK3 immunoreactivity, vented Aβ -induced morphological changes, specifically 1−42 suggesting increases in both GSK3 levels and activity as shrunken soma and affected dendritic and axonal processes, disease pathology progressed. Stage V/VI brains exhibited and reduced Aβ-induced decreases in cell viability of primary AT8 immunoreactivity and tangle inclusions throughout rat hippocampal neuronal cultures [33]. After injection of the entorhinal and temporal cortices and the hippocampus. Aβ into rat hippocampus, increased GSK3 immunoreactivity Most inclusion-positive neurons stained intensely for active was found near Aβ deposits [33]. Treatment with SB216763 GSK3, while little or no inactive GSK3 immunoreactivity was or GSK inhibitor VIII also prevented Aβ-induced caspase-3 recorded in cortical or hippocampal tissues. Collectively, Pei activation in vivo, decreased TUNEL positive neurons, pre- and colleagues [18] clearly defined an Alzheimer’s disease vented tau-phosphorylation, reduced microglia activation, progression profile detailing increased tau phosphorylation decreased cytochrome c release from the mitochondria to and increased GSK3β expression and activity in cortical the cytosol, and improved deficits in the Morris water maze and hippocampal tissues as disease pathology worsened. [27, 28]. GSK3 inhibitor VIII or lithium reduced Aβ - 1–42 Ferrer and colleagues [19] also found increased GSK3 induced reduction in cell viability and reduced markers immunoreactivity in degenerating neurons characterized by of apoptosis [28]. Lithium treatment decreased cortical tangle-like inclusions in Stage III and Stage VI postmortem tau phosphorylation and aggregates, and reduced axonal Alzheimer’s disease entorhinal cortex and hippocampus. degeneration [34]. Administration of the GSK3 inhibitor Furthermore, GSK3 colocalized with 40–80% of neurons NP12 decreased tau phosphorylation, decreased Aβ deposi- with hyperphosphorylated tau (PHF-1 antibody), thereby tion, and improved performance in the Morris water maze supporting the notion that GSK3 expression and/or activity in amyloid precursor protein (APP) transgenic mice, and increases as Alzheimer’s disease progresses. reduced neuronal loss in the CA1 region of the hippocampus GSK3 immunoreactivity has been reported to be in- and the entorhinal cortex [35]. Rockenstein and colleagues creased at sites of granulovacular degeneration, a patho- [36] also reported neuroprotective effects of inhibiting GSK3 logical characteristic of Alzheimer’s disease [15, 19, 20]. with lithium using APP transgenic mice, with improvements Leroy and colleagues [20] reported increased GSK3β and in the Morris water maze task, decreased Aβ immunore- phospho-tyr216-GSK3β immunoreactivity in neuronal cell activity, decreased phospho-tau immunoreactivity, and an bodies and dendrites of postmortem human hippocampal increase in MAP2 staining (indicative of increased neuron 4 International Journal of Alzheimer’s Disease density) after treatment with lithium. The role of GSK3 was increased caspase-3 activation [49]. In HEK293 and SK- further examined by crossing mice conditionally expressing N-MC cells, Kwok and colleagues [50] transiently over- a dominant-negative (DN) GSK3β construct with hAPP expressed GSK3βΔexon9+11, which lacks exons 9 and 11 and transgenic mice. These hAPP x DN-GSK3β mice displayed is characterized by an increased propensity to phosphorylate improved performance in the Morris water maze, increased tau, and found decreased β-catenin levels and signaling. MAP2 immunoreactivity, decreased Aβ immunoreactivity, Transient transfection of tau decreased β-catenin levels decreased phospho-tau immunoreactivity, and normal cell by 25%, and co-expression of tau and GSK3βΔexon9+11 morphologies, when compared to hAPP transgenic litter- reversed the GSK3-mediated decrease in β-catenin signal- mates, suggesting that inhibition of GSK3 can phenotypically ing. Inestrosa and colleagues have reported in detail that rescue hAPP mice [36]. Ma and colleagues [37] showed that activation of Wnt signaling, which inhibits GSK3-mediated antibodies directed against Aβ increased inhibitory serine- phosphorylation and degradation of β-catenin, is neuro- phosphorylation of GSK3, which was associated with a protective against Aβ toxicity [33, 51–53]. Thus, reduced decrease in neurotoxicity. Altogether, these and additional levels of Wnt signalling-associated β-catenin may contribute reports have firmly established that Aβ activates GSK3 and to GSK3-mediated neurotoxicity induced by Aβ produc- that reducing GSK3 activity provides protection from Aβ- tion and promoted by mutations in PS1 in Alzheimer’s induced neurotoxicity. disease. Studies of the mechanism by which Aβ activates GSK3 have indicated the involvement of the PI3K-Akt 3.4. Toxicity Associated with Tau. The microtubule-associat- pathway, which normally maintains inhibitory serine- ed protein tau is one of the most well characterized substrates phosphorylation of GSK3. Aβ treatment was shown to cause of GSK3 [54]. Phosphorylation of tau by GSK3 promotes tau time-dependent decreases in PI3K activity and increases dissociation from microtubules, increasing destabilization of in GSK3 activity [22]. Treatment of cultured cells with microtubules [55]. Conversely, inhibition of GSK3 promotes Aβ reduced Akt phosphorylation, indicative of decreased 1–42 tau binding to microtubules and assembly of microtubules Akt activity [38, 39], activated GSK3β [38], and activated [56]. As noted above, several studies have reported that caspase-3 [25], suggesting that decreased Akt activity con- the GSK3-mediated increase in tau phosphorylation in tributes to Aβ-induced activation of GSK3, which promotes Alzheimer’s disease may result in part from Aβ-induced apoptosis. activation of GSK3. GSK3-mediated tau phosphorylation In addition to acting downstream of Aβ in its neurotoxic in Alzheimer’s disease has been suggested to promote tau signaling, GSK3 likely also influences the neurotoxicity of oligomerization, which can be toxic [57, 58], and aggregation Aβ by regulating APP processing and the production of Aβ. of tau and eventual neurodegeneration [54, 59]. Sahara Takashima and colleagues [24]found that GSK3β associated and colleagues [60] reported that overexpression of tau in with presenilin-1 in postmortem Alzheimer’s disease cortical SH-SY5Y cells resulted in increased tau phosphorylation tissues and in COS-7 cells transiently transfected with wild- and increased caspase-3 activity, suggesting a role in pro- type presenilin-1, which raised the possibility that GSK3 apoptotic signaling and cell death. It is possible that GSK3β- may regulate Aβ production. This was found in studies that mediated hyperphosphorylation of tau may promote tau- showed reducing GSK3 activity in vitro or in vivo diminished mediated, as well as Aβ-mediated, neurotoxicity. the production of Aβ [40–42]. The mechanism by which GSK3 promotes Aβ production remains to be determined, Transgenic mice have also been used to study the inter- but may be related to its phosphorylation and regulation of actions between tau and GSK3. Using protein preparations presenilin-1 [24, 43]or of APP [44]. from the brains and spinal cords of double transgenic mice β-Catenin destabilization has been suggested to be a over-expressing GSK3β and human tau40-1, an isoform of contributing factor in Aβ-induced GSK3-mediated neuro- tau containing an additional 29 and 58 amino acid sequence toxicity. GSK3 promotes the degradation of β-catenin, and that promotes Alzheimer’s disease-like pathologies [61], nuclear β-catenin levels were decreased in response to acute Spittaels and colleagues [8] found decreased tau binding Aβ treatments, indicating that Aβ-induced activation of to microtubules in double transgenic mice, as compared GSK3 led to increased degradation of β-catenin [45, 46]. to transgenic mice littermates expressing human tau40-1 Lucas and colleagues [10] reported decreased nuclear β- alone. The relationship between GSK3 and tau was found catenin levels in GSK3 over-expressing mice. Presenilin- to be more than a mere protein-protein interaction, as 1 (PS1), a GSK3 substrate, can regulate the turnover of Kwok and colleagues [50] found interactions between the β-catenin [47, 48]. Kang and colleagues [48]found that GSK3β and tau (MAPT) genes associated with increased GSK3 co-immunoprecipitated with PS1 but not with mutant risk and incidence of Alzheimer’s disease. Using senescence- M146L or ΔX9 PS1. Overexpression of PS1 also increased accelerated mice (SAM), Tajes and colleagues [62]showed the GSK3β-β-catenin association, thereby facilitating GSK3- that inhibition of GSK3 with lithium decreased calpain mediated phosphorylation and subsequent degradation of activation and decreased caspase-3 activity. Primary neu- β-catenin. PS1 mutants were later linked to increased ronal cultures treated with the GSK3 inhibitors lithium or GSK3 activity via decreased PI3K/Akt signaling, thereby SB415286 exhibited decreased neurite disintegration, neu- promoting decreased inhibitory serine-phosphorylation of ronal shrinkage, and nuclear condensation, further impli- GSK3 in primary neuronal cultures [49]. In cultured cating GSK3 in neurodegenerative disease progression [62]. −/− PS1 neurons the activated GSK3 was associated with In transgenic mice expressing mutant tau, chronic lithium International Journal of Alzheimer’s Disease 5 treatment reduced tau aggregation [63]. Evidence of tau- oxidative stress-induced cell death [2]. For example, Schafer related toxicity has been bolstered by studies of tau-knockout and colleagues [74] found that resistance to oxidative stress mice [64]. Mice conditionally over-expressing GSK3 and was associated with decreased GSK3 activity. Aβ treatment lacking tau performed better in the Morris water maze of cells increases oxidative stress [75, 76], as well as activates task, as compared to GSK3 over-expressing littermates [64]. GSK3, which may contribute to apoptosis. Several reports Knockout of tau reduced GSK3-mediated shrinkage of the showed that GSK3 inhibitors reduce toxicity of oxidative dentate gyrus and reduced reactive microglia, as GSK3-only stress [77, 78]. Thus, inhibition of GSK3 may be neuropro- over-expressing littermates were characterized by increased tective in Alzheimer’s disease in part by reducing oxidative brain shrinkage and increased reactive microglia compared stress-induced neurotoxicity. to control and tau-knockout mice. Neurotrophic factor deficiency has been linked with In addition to hyperphosphorylation of tau, GSK3 has neuronal loss in Alzheimer’s disease. Studies of insulin- also been linked to alternate splicing of tau, thereby possibly like growth factor-I (IGF-1) are particularly interesting promoting pro-apoptotic oligomerization and tau-induced because IGF-1 deficiency has been linked to Alzheimer’s cell death [65]. Inclusionof exon10 likely promotes disease and IGF-1-induced cellular signaling contributes to increased binding of tau and stabilization of microtubules, maintaining inhibition of GSK3 by activating the PI3K- thereby combating tau aggregate-mediated neurofibril- Akt pathway. Additionally, GSK3 inhibition has been linked lary tangle formation and neurodegeneration observed in to increases in IGF-I in the brain [79]. Bolos ´ and col- Alzheimer’s disease. Hernandez ´ and colleagues [65]exam- leagues [79] used megalin, an IGF-I receptor interacting ined the relationship between GSK3 and alternative splicing protein that is associated with transport of IGF-1, and of tau and found that in primary mouse cortical neurons found that in MDCK cells transiently transfected with or treatment with GSK3 inhibitors lithium or AR-A014418 without mini-megalin, a cDNA encoding the two peri- decreased alternative splicing of tau and promoted the membrane extracellular cysteine-rich domains, the trans- increased presence of exon 10 in tau, which promotes micro- membrane region, and the cytoplasmic region of the megalin tubule bundling and stabilization, as compared to exon 10- gene, treatment with the GSK3 inhibitor NP12 stimulated absent tau [65, 66]. Alternative splicing of tau has also been internalization of IGF-I and cell-surface megalin expression. linked to caspase-mediated cleavage and aggregation of tau Moreover, treatment of APP/PS1 transgenic mice with in Alzheimer’s disease [67]. Alternative forms of tau have NP12 significantly increased both brain and CSF IGF-I been linked to increased tau aggregation in other cells and levels. Collectively this data suggests that inhibition of cell systems [68]. over-active GSK3β that appears to occur in Alzheimer’s In contrast to reports of tau oligomerization contributing disease can promote IGF-I expression and counteract Aβ- to neurotoxicity, a few reports suggest a neuroprotec- induced toxicity. Brain-derived neurotrophic factor (BDNF) tive role for tau. Mouse neuroblastoma cells stably over- activation of TrkB receptors is also responsible for activation expressing tau were less affected by apoptotic stimuli, includ- of the PI3K/Akt pathway and inhibition of GSK3β via Ser9 ing staurosporine, camptothecin, and H O treatments, and phosphorylation [80–82]. Decreases in hippocampal and 2 2 over-expressed tau blocked GSK3 overexpression-mediated cortical BDNF levels have been reported in Alzheimer’s increases in cell death, actions that may have resulted disease [83–85], which could promote an increase in GSK3 from tau binding to GSK3 to block its induction of β- activity. Elliott and colleagues [85] showed that in neuronally catenin degradation, allowing up-regulated levels of β- differentiated P19 mouse embryonic carcinoma cells, BDNF catenin, which supports cell survival [69]. Recently, Wang altered tau phosphorylation, and that inhibition of GSK3 and colleagues [70] found that overexpression of human tau, with lithium reduced tau phosphorylation. BDNF has also in vivo in transgenic mice and in vitro in N2a cells, decreased been linked to promotion of anti-apoptotic signaling via p53 levels, decreased mitochondrial cytochrome c release, the PI3K/Akt pathway. Hetman and colleagues [86]found and decreased caspase-9 and caspase-3 activation. Treatment that trophic factor withdrawal promoted inhibition of the with lithium exaggerated the decrease in p53 expression and cell survival mediator PI3K and activated the pro-apoptotic increased pro-apoptotic processes [70]. Thus, the connec- GSK3, which was reversed by PI3K activating treatments, tions between tau and GSK3 in affecting neurodegeneration such as BDNF, by treatment with a GSK3 inhibitor, or remain to be further clarified and may be complicated by after transient transfection of a kinase-dead GSK3 mutant. employing overexpression approaches. Overexpression of wild-type or mutant β-catenin, in which all GSK3β-targeted serines were mutated to alanines, had no effect on GSK3β-mediated neuronal apoptosis [86]. 3.5. GSK3 Promotes Insults Associated with Alzheimer’s Dis- Thus, neurotrophin deficiency in Alzheimer’s disease may ease. As previously reviewed [2], GSK3 promotes apoptosis contribute to abnormally active GSK3 that can promote induced by many insults that activate the intrinsic apop- neurotoxicity. totic signaling pathway, some of which may contribute to neuronal loss in Alzheimer’s disease. For example, oxidative stress is increased in Alzheimer’s disease, as indicated by 3.6. Mechanisms by Which GSK3 May Impede Cell Survival increased markers of oxidative stress found in postmortem from Insults. GSK3 has been reported to promote apoptosis Alzheimer’s disease brain [71–73], and has been associated by regulating the actions of proteins involved in apoptosis with the loss of neuronal viability, and GSK3 promotes signaling and by regulating transcription factors known to 6 International Journal of Alzheimer’s Disease regulate the expression of apoptosis modulators. For exam- identified in Lafora Disease, an autosomal recessive form ple, GSK3 has been reported to regulate Bax, a pro-apoptotic of progressive myoclonus epilepsy that is characterized Bcl2 family member that is commonly associated with by dementia and rapid neurological deterioration [102]. the release of cytochrome c. Under apoptotic conditions, Amyotrophic lateral sclerosis has been linked to mutations Bax undergoes a conformational change associated with its in superoxide dismutase type 1 (SOD1), and expression of translocation from the cytosol to the mitochondria where mutant SOD1 in motor neurons increased GSK3 activity and it facilitates cytochrome c release in apoptotic signaling apoptosis, and GSK3 inhibitors provided protection from [87–89]. GSK3 can directly phosphorylate Bax on Ser-163, apoptosis [77]. Thus, there appear to be a variety of disease- which results in the activation of Bax [90] and inhibition of associated conditions that can cause abnormal activation of GSK3 with lithium prevented Bax activation and subsequent GSK3 that contributes to the neurodegenerative process. cytochrome c release [91]. Another Bcl2 family member, Mcl-1, an anti-apoptotic protein that can be induced after 4. GSK3 Impedes Extrinsic Apoptotic Signaling cellular stress to promote cell survival, is phosphorylated on Ser159 by GSK3 to promote Mcl1 degradation, thereby In contrast to the many studies of intrinsic apoptotic reducing the protective action of Mcl-1 [92, 93]. By these signaling mechanisms in association with loss of cell via- and other actions on the apoptotic signaling pathway, GSK3 bility in Alzheimer’s disease, few studies have addressed can reduce cellular resilience to stress and promote apoptotic the possibility that death receptor-mediated extrinsic apop- signaling. totic signaling is involved in Alzheimer’s disease. Plasma Several transcription factors that are inhibited by GSK3 membrane death receptors that can initiate apoptosis are normally promote mechanisms that promote cellular sur- members of the tumor necrosis factor (TNF) receptor vival responses to stresses that are potentially lethal insults family that contain conserved intracellular death domains, [1]. These include heat shock factor protein 1 (HSF-1), which includes Fas (CD95/Apo1), TNF-R1 (p55/CD120a), cyclic AMP response element-binding protein (CREB), and TNF-related apoptosis-inducing ligand receptor-1 (TRAIL- others, impairments of which are well-documented to R1/DR4), and TRAIL-R2 (DR5/Apo2/TRICK2/KILLER). increase the susceptibility of cells to toxic insults. HSF-1, for Studies in postmortem Alzheimer’s disease brain and par- example, promotes the expression of heat shock proteins, ticularly in Aβ-treated cells in vitro have provided some chaperones that combat cellular stress. Chu and colleagues evidence for increased death receptor-induced apoptotic [94] reported that GSK3 reduced HSF-1 activity and signaling pathway [103–111]. However, the contribution increased susceptibility to environmental stressors. Xavier of death receptor-initiated apoptosis in Alzheimer’s disease and colleagues [95] showed that overexpression of GSK3β remains to be firmly established. repressed HSF-1 transcriptional activity and DNA-binding. Although it remains unclear if death receptors contribute CREB, which can support cell survival and is activated by to cell loss in Alzheimer’s disease, we can surmise that phosphorylation at Ser133, also can be negatively regulated GSK3 is highly unlikely to contribute to this potential by GSK3 [1, 96]. Activation of CREB has been reported to neuropathological mechanism. This is because GSK3 impairs be impaired in Alzheimer’s disease hippocampal tissues [97, death receptor-induced apoptotic signaling, as opposed to its 98]. Since GSK3 inhibits CREB activity [1, 96, 99], increased promotion of intrinsic apoptotic signaling [2]. The concept GSK3 activity may contribute to the Alzheimer’s disease- that GSK3 inhibits death receptor-induced apoptosis fol- induced decrease of phospho-CREB-mediated neuroprotec- lowed the discovery that GSK3β knockout mice died during tion. Thus, by regulating these and other transcription fac- embryonic development due to massive hepatocyte apoptosis tors that influence the expression of proteins that modulate [112], which demonstrated that GSK3β is an important cellular responses to stress [1], GSK3 may contribute to inhibitor of TNFα-induced apoptosis. This inhibitory effect setting the threshold for apoptotic signaling, which may be of GSK3 on extrinsic apoptotic signaling was extended to all lowered in Alzheimer’s disease. other death receptors, as reviewed [2]. The mechanism for this action was found to be due to the presence of GSK3 in a death receptor-associated anti-apoptotic complex that 3.7. GSK3 Promotes Decreased Cell Survival in Other Neurode- impedes the initiation of apoptotic signaling [113]. Thus, generative Diseases. Many components of neurodegenerative several studies have clearly established that GSK3 is anti- processes are common among various neurodegenerative apoptotic in death receptor-mediated signaling. diseases, including apoptosis and mechanisms regulating If death receptor-induced apoptosis does contribute to apoptosis. Thus, it is not surprising that, similarly with cell loss in Alzheimer’s disease, the anti-apoptotic action of Alzheimer’s disease, GSK3 has also been linked to neuronal GSK3 in this process could very likely limit the application of death in other neurological diseases. For example, prion inhibitors of GSK3 as therapeutic agents in Alzheimer’s dis- disease shares with Alzheimer’s disease accumulations of ease because they would be able to promote extrinsic apop- protein aggregates and neuronal death [100, 101]. Mouse totic signaling. This complication was exquisitely demon- embryonic cortical neurons (E17) treated with varying strated in a study of the effects of in vivo treatment with concentrations of prion protein (PrP) peptide exhibited the GSK3 inhibitor lithium, which demonstrated increased increased GSK3 activity and increased tau phosphorylation, neuronal apoptosis mediated by lithium’s promotion of Fas- which was prevented by pretreatment with lithium. GSK3β mediated apoptotic signaling [114]. Whetherornot this activation and hyperphosphorylation of tau has also been detrimental action of GSK3 inhibitors would be deleterious International Journal of Alzheimer’s Disease 7 in Alzheimer’s disease depends on whether death receptor- [9] K. Spittaels, C. Van den Haute, J. Van Dorpe et al., “Neonatal neuronal overexpression of glycogen synthase kinase-3β induced apoptotic pathways are activated in Alzheimer’s reduces brain size in transgenic mice,” Neuroscience, vol. 113, disease, a question that remains unresolved. no. 4, pp. 797–808, 2002. [10] J. J. Lucas, F. Hernand ´ ez, P. Gome ´ z-Ramos, M. A. Moran, ´ R. 5. Conclusions Hen, and J. Avila, “Decreased nuclear β-catenin, tau hyper- phosphorylation and neurodegeneration in GSK-3β condi- GSK3 has been shown to be associated with the major tional transgenic mice,” EMBO Journal, vol. 20, no. 1-2, pp. neuropathological markers of Alzheimer’s disease and to be 27–39, 2001. abnormally activated or expressed in Alzheimer’s disease [11] F. Hernand ´ ez, J. Borrell, C. Guaza, J. Avila, and J. J. Lucas, brains, particularly in association with neuropathological “Spatial learning deficit in transgenic mice that conditionally or degenerative markers. GSK3 is activated by Aβ and over-express GSK-3β in the brain but do not form tau promotes both Aβ production and its neurotoxic actions. filaments,” Journal of Neurochemistry, vol. 83, no. 6, pp. 1529– GSK3 phosphorylates tau and may promote oligomeriza- 1533, 2002. [12] T. Engel, F. Hernand ´ ez, J. Avila, and J. J. Lucas, “Full reversal tion of tau and its aggregation, which can contribute to of Alzheimer’s disease-like phenotype in a mouse model with neurotoxicity. Apoptosis may contribute to neuronal loss in conditional overexpression of glycogen synthase kinase-3,” Alzheimer’s disease, and GSK3 promotes intrinsic apoptotic Journal of Neuroscience, vol. 26, no. 19, pp. 5083–5090, 2006. signaling induced by many insults, some of which may be [13] T. Engel, J. J. Lucas, P. Gome ´ z-Ramos, M. A. Moran, J. involved in neurodegeneration in Alzheimer’s disease. GSK3 Avila, and F. Hernandez, “Cooexpression of FTDP-17 tau and promotes intrinsic apoptotic signaling both by regulating GSK-3β in transgenic mice induce tau polymerization and signaling proteins involved in apoptosis and regulating neurodegeneration,” Neurobiology of Aging, vol. 27, no. 9, pp. transcription factors that control the expression of proteins 1258–1268, 2006. that modulate cellular responses to stress. Altogether, much [14] B. Li, J. Ryder, Y. Su et al., “Overexpression of GSK3β resulted evidence indicates that GSK3 is an integral component of the in tau hyperphosphorylation and morphology reminiscent of neurodegenerative processes in Alzheimer’s disease. pretangle-like neurons in the brain of PDGSK3β transgenic mice,” Transgenic Research, vol. 13, no. 4, pp. 385–396, 2004. [15] T. Ishizawa, N. Sahara, K. Ishiguro et al., “Co-localization of Acknowledgment glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice,” American The authors’ research was supported by grants from the Journal of Pathology, vol. 163, no. 3, pp. 1057–1067, 2003. NIMH (MH092970, MH090236, and MH038752). [16] J. Avila, E. Go´ mez De Barreda, T. Engel et al., “Tau kinase i overexpression induces dentate gyrus degeneration,” References Neurodegenerative Diseases, vol. 7, no. 1–3, pp. 13–15, 2010. [17] J. J. Pei, T. Tanaka, Y. C. Tung, E. Braak, K. Iqbal, and I. [1] C. A. Grimes and R. S. Jope, “The multifaceted roles of Grundke-Iqbal, “Distribution, levels, and activity of glycogen glycogen synthase kinase 3β in cellular signaling,” Progress in synthase kinase-3 in the Alzheimer disease brain,” Journal of Neurobiology, vol. 65, no. 4, pp. 391–426, 2001. Neuropathology and Experimental Neurology, vol. 56, no. 1, [2] E. Beurel and R. S. Jope, “The paradoxical pro- and anti- pp. 70–78, 1997. apoptotic actions of GSK3 in the intrinsic and extrinsic [18] J. J. Pei, E. Braak, H. Braak et al., “Distribution of active apoptosis signaling pathways,” Progress in Neurobiology,vol. glycogen synthase kinase 3β (GSK-3β)in brains staged 79, no. 4, pp. 173–189, 2006. for Alzheimer disease neurofibrillary changes,” Journal of [3] W. C. Earnshaw, L. M. Martins, and S. H. Kaufmann, Neuropathology and Experimental Neurology, vol. 58, no. 9, “Mammalian caspases: structure, activation, substrates, and pp. 1010–1019, 1999. functions during apoptosis,” Annual Review of Biochemistry, [19] I. Ferrer, M. Barrachina, and B. Puig, “Glycogen synthase vol. 68, pp. 383–424, 1999. kinase-3 is associated with neuronal and glial hyperphos- [4] M. O. Hengartner, “The biochemistry of apoptosis,” Nature, phorylated tau deposits in Alzheimer’s diasese, Pick’s disease, vol. 407, no. 6805, pp. 770–776, 2000. progressive supranuclear palsy and corticobasal degenera- [5] A.Ashkenazi and V.M.Dixit, “Death receptors: signaling tion,” Acta Neuropathologica, vol. 104, no. 6, pp. 583–591, and modulation,” Science, vol. 281, no. 5381, pp. 1305–1308, [20] K. Leroy, A. Boutajangout, M. Authelet, J. R. Woodgett, [6] M. Pap and G. M. Cooper, “Role of glycogen synthase kinase- B. H. Anderton, and J.-P. Brion, “The active form of 3 in the phosphatidylinositol 3- kinase/Akt cell survival glycogen synthase kinase-3β is associated with granulovac- pathway,” JournalofBiologicalChemistry, vol. 273, no. 32, pp. uolar degeneration in neurons in Alzheimers’s disease,” Acta 19929–19932, 1998. Neuropathologica, vol. 103, no. 2, pp. 91–99, 2002. [7] G. N. Bijur,P.De Sarno, and R. S. Jope,“Glycogen synthase [21] A. Takashima, K. Noguchi, K. Sato, T. Hoshino, and K. kinase-3β facilitates staurosporine- and heat shock- induced Imahori, “tau Protein kinase I is essential for amyloid β- apoptosis. Protection by lithium,” Journalof BiologicalChem- protein-induced neurotoxicity,” Proceedings of the National istry, vol. 275, no. 11, pp. 7583–7590, 2000. Academy of Sciences of the United States of America, vol. 90, [8] K. Spittaels, C. Van Den Haute, J. Van Dorpe et al., “Glycogen no. 16, pp. 7789–7793, 1993. synthase kinase-3β phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four- [22] A. Takashima, K. Noguchi, G. Michel et al., “Exposure of rat hippocampal neurons to amyloid β peptide (25-35) induces repeat tau transgenic mice,” Journal of Biological Chemistry, vol. 275, no. 52, pp. 41340–41349, 2000. the inactivation of phosphatidyl inositol-3 kinase and the 8 International Journal of Alzheimer’s Disease activation of tau protein kinase I/glycogen synthase kinase- [37] Q. L. Ma, G.P.Lim, M.E.Harris-White et al., “Antibodies 3β,” Neuroscience Letters, vol. 203, no. 1, pp. 33–36, 1996. against β-amyloid reduce Aβ oligomers, glycogen synthase [23] A. Takashima, T. Honda, K. Yasutake et al., “Activation kinase-3β activation and τ phosphorylation in vivo and in of tau protein kinase I/glycogen synthase kinase-3β by vitro,” Journal of Neuroscience Research,vol.83, no.3,pp. amyloid β peptide (25-35) enhances phosphorylation of tau 374–384, 2006. in hippocampal neurons,” Neuroscience Research, vol. 31, no. [38] W. Wei, X. Wang, and J. W. Kusiak, “Signaling events in 4, pp. 317–323, 1998. amyloid β-peptide-induced neuronal death and insulin-like [24] A. Takashima, M. Murayama, O. Murayama et al., “Presenilin growth factor I protection,” JournalofBiologicalChemistry, 1 associates with glycogen synthase kinase-3β and its sub- vol. 277, no. 20, pp. 17649–17656, 2002. strate tau,” Proceedings of the National Academy of Sciences of [39] T. Suhara, J. Magrane, K. Rosen et al., “Aβ42 generation the United States of America, vol. 95, no. 16, pp. 9637–9641, is toxic to endothelial cells and inhibits eNOS function 1998. through an Akt/GSK-3β signaling-dependent mechanism,” [25] A. Cedazo-M´ınguez, B.O. Popescu,J.M. Blanco-Millan ´ et Neurobiology of Aging, vol. 24, no. 3, pp. 437–451, 2003. al., “Apolipoprotein E and β-amyloid (1-42) regulation of [40] C. J. Phiel, C. A. Wilson, V.M.Y. Lee, and P.S.Klein,“GSK- glycogen synthase kinase-3β,” Journal of Neurochemistry,vol. 3α regulates production of Alzheimer’s disease amyloid-β 87, no. 5, pp. 1152–1164, 2003. peptides,” Nature, vol. 423, no. 6938, pp. 435–439, 2003. [26] A. R. Alvarez, J. A. Godoy, K. Mullendorff,G.H.Olivares, [41] X. Sun, S. Sato, O. Murayama et al., “Lithium inhibits M. Bronfman, and N. C. Inestrosa, “Wnt-3a overcomes β- amyloid secretion in COS7 cells transfected with amyloid amyloid toxicity in rat hippocampal neurons,” Experimental precursor protein C100,” Neuroscience Letters, vol. 321, no. Cell Research, vol. 297, no. 1, pp. 186–196, 2004. 1-2, pp. 61–64, 2002. [27] S. Hu, A.N. Begum,M.R. Jones et al., “GSK3inhibitors [42] Y. Su,J.Ryder, B.Liet al., “Lithium, acommon drug for show benefits inanAlzheimer’s disease (AD) model of bipolar disorder treatment, regulates amyloid-β precursor neurodegeneration but adverse effects in control animals,” protein processing,” Biochemistry, vol. 43, no. 22, pp. 6899– Neurobiology of Disease, vol. 33, no. 2, pp. 193–206, 2009. 6908, 2004. [28] S. H. Koh, M. Y. Noh, and S.H.Kim,“Amyloid-beta-induced [43] F. Kirschenbaum, S. C. Hsu,B.Cordell, and J. V.McCarthy, neurotoxicity is reduced by inhibition of glycogen synthase “Glycogen synthase kinase-3β regulates presenilin 1 C- kinase-3,” Brain Research, vol. 1188, no. 1, pp. 254–262, 2008. terminal fragment levels,” Journalof BiologicalChemistry,vol. [29] G. Alvarez, J. R. Munoz- ˜ Montano ˜ , J. Satru´ stegui, J. Avila, E. 276, no. 33, pp. 30701–30707, 2001. Bogone ´ z, and J. D´ıaz-Nido, “Lithium protects cultured neu- [44] A. E. Aplin, J. S. Jacobsen, B. H. Anderton, and J. M. rons against β-amyloid-induced neurodegeneration,” FEBS Gallo, “Effect of increased glycogen synthase kinase-3 activity Letters, vol. 453, no. 3, pp. 260–264, 1999. upon the maturation of the amyloid precursor protein in [30] A. Ferreira, Q. Lu, L. Orecchio, and K. S. Kosik, “Selective transfected cells,” NeuroReport, vol. 8, no. 3, pp. 639–643, phosphorylation of adult tau isoforms in mature hippocam- 1997. pal neurons exposed to fibrillar aβ,” Molecular and Cellular [45] Z. Zhang, H. Hartmann, V. M. Do et al., “Destabilization of Neurosciences, vol. 9, no. 3, pp. 220–234, 1997. β-catenin by mutations in presenilin-1 potentiates neuronal [31] A. Takashima, H. Yamaguchi, K. Noguchi et al., “Amyloid, apoptosis,” Nature, vol. 395, no. 6703, pp. 698–702, 1998. β peptide induces cytoplasmic accumulation of amyloid [46] C. C. Weihl, G. D. Ghadge, S.G.Kennedy, N. Hay,R. J. Miller, protein precursor via tau protein kinase I/glycogen synthase and R. P. Roos, “Mutant presenilin-1 induces apoptosis and kinase-3β in rat hippocampal neurons,” Neuroscience Letters, downregulates Akt/PKB,” Journal of Neuroscience,vol.19, no. vol. 198, no. 2, pp. 83–86, 1995. 13, pp. 5360–5369, 1999. [32] H. Wei, P. R. Leeds, Y. Qian,W.Wei,R. W.Chen, and DE. [47] C. Twomey and J. V. McCarthy, “Presenilin-1 is an unprimed M. Chuang, “β-amyloid peptide-induced death of PC 12 cells glycogen synthase kinase-3β substrate,” FEBS Letters,vol. and cerebellar granule cell neurons is inhibited by long-term 580, no. 17, pp. 4015–4020, 2006. lithium treatment,” European Journal of Pharmacology,vol. [48] D. E. Kang,S.Soriano, M. P.Frosch et al.,“Presenilin 1 392, no. 3, pp. 117–123, 2000. facilitates the constitutive turnover of β-catenin: differential [33] N. C. Inestrosa, G. V. De Ferrari, J. L. Garrido et al., “Wnt activity of Alzheimer’s disease-linked PS1 mutants in the β- signaling involvement in β-amyloid-dependent neurodegen- catenin-signaling pathway,” Journal of Neuroscience, vol. 19, eration,” Neurochemistry International,vol.41, no.5,pp. no. 11, pp. 4229–4237, 1999. 341–344, 2002. [49] L. Baki, R. L. Neve, Z. Shao,J.Shioi,A. Georgakopoulos, and [34] W. Noble, E. Planel, C. Zehr et al., “Inhibition of glycogen N. K. Robakis, “Wild-type but not FAD mutant presenilin- synthase kinase-3 by lithium correlates with reduced tauopa- 1 prevents neuronal degeneration by promoting phos- thy and degeneration in vivo,” Proceedings of the National phatidylinositol 3-kinase neuroprotective signaling,” Journal Academy of Sciences of the United States of America, vol. 102, of Neuroscience, vol. 28, no. 2, pp. 483–490, 2008. no. 19, pp. 6990–6995, 2005. [50] J. B. J. Kwok, C.T.Loy,G.Hamilton etal.,“Glycogen synthase [35] L. Sereno´, M. Coma,M.Rodr´ıguez et al., “A novel GSK- kinase-3β and tau genes interact in Alzheimer’s disease,” 3β inhibitor reduces Alzheimer’s pathology and rescues Annals of Neurology, vol. 64, no. 4, pp. 446–454, 2008. neuronal loss in vivo,” Neurobiology of Disease, vol. 35, no. [51] G. V. De Ferrari, M. A. Chacon, M. I. Barria et al., “Activation 3, pp. 359–367, 2009. of Wnt signaling rescues neurodegeneration and behavioral [36] E. Rockenstein, M. Torrance, A. Adame et al., “Neuroprotec- impairments induced by β-amyloid fibrils,” Molecular Psychi- tive effects of regulators of the glycogen synthase kinase-3β atry, vol. 8, no. 2, pp. 195–208, 2003. signaling pathway in a transgenic model of Alzheimer’s dis- [52] R. A. Fuentealba, G. Farias, J. Scheu, M. Bronfman, M. P. ease are associated with reduced amyloid precursor protein Marzolo, and N. C. Inestrosa, “Signal transduction during phosphorylation,” Journal of Neuroscience,vol. 27, no.8,pp. amyloid-β-peptide neurotoxicity: role in Alzheimer disease,” 1981–1991, 2007. Brain Research Reviews, vol. 47, no. 1–3, pp. 275–289, 2004. International Journal of Alzheimer’s Disease 9 [53] W. Cerpa, E. M. Toledo, L. Varela-Nallar, and N. C. Inestrosa, involved in Alzheimer’s nerodegeneration,” Proceedings of the “The role of WNT signaling in neuroprotection,” Drug News National Academy of Sciences of the United States of America, and Perspectives, vol. 22, no. 10, pp. 579–591, 2009. vol. 104, no. 9, pp. 3591–3596, 2007. [54] P. J. Dolan and G. V. W. Johnson, “The role of tau kinases in [70] H.-H. Wang, H.-L. Li, R. Liu et al., “Tau overexpression Alzheimer’s disease,” Current Opinion in Drug Discovery and inhibits cell apoptosis with the mechanisms involving mul- Development, vol. 13, no. 5, pp. 595–603, 2010. tiple viability-related factors,” Journal of Alzheimer’s Disease, [55] K. Ishiguro, A. Omori, M. Takamatsu et al., “Phosphoryla- vol. 21, no. 1, pp. 167–179, 2010. tion sites on tau by tau protein kinase I, a bovine derived [71] M. A. Pappolla,Y.J.Chyan,R. A.Omar et al., “Evidence kinase generating an epitope of paired helical filaments,” of oxidative stress and in vivo neurotoxicity of β-amyloid in Neuroscience Letters, vol. 148, no. 1-2, pp. 202–206, 1992. a transgenic mouse model of Alzheimer’s disease: a chronic [56] M. Hong, D. C.R. Chen, P. S. Klein, and V.M.Y.Lee, oxidative paradigm for testing antioxidant therapies in vivo,” “Lithium reduces tau phosphorylation by inhibition of American Journal of Pathology, vol. 152, no. 4, pp. 871–877, glycogen synthase kinase-3,” Journal of Biological Chemistry, 1998. vol. 272, no. 40, pp. 25326–25332, 1997. [72] D. Galasko and T. J. Montine, “Biomarkers of oxidative dam- [57] J. Avila, J. J. Lucas, M. Per ´ ez, and F. Hernand ´ ez, “Role of tau age and inflammation in Alzheimers disease,” Biomarkers in protein in both physiological and pathological conditions,” Medicine, vol. 4, no. 1, pp. 27–36, 2010. Physiological Reviews, vol. 84, no. 2, pp. 361–384, 2004. [73] M. Padurariu, A. Ciobica, L. Hritcu, B. Stoica, W. Bild, and [58] K. Santacruz, J. Lewis, T. Spires et al., “Medicine: tau C. Stefanescu, “Changes of some oxidative stress markers in suppression in a neurodegenerative mouse model improves the serum of patients with mild cognitive impairment and memory function,” Science, vol. 309, no. 5733, pp. 476–481, Alzheimer’s disease,” Neuroscience Letters, vol. 469, no. 1, pp. 2005. 6–10, 2010. [59] K. Imahori and T. Uchida, “Physiology and pathology of tau [74] M. Schaf ¨ er, S. Goodenough, B. Moosmann, and C. Behl, protein kinases in relation to Alzheimer’s disease,” Journal of “Inhibition of glycogen synthase kinase 3β is involved in the Biochemistry, vol. 121, no. 2, pp. 179–188, 1997. resistance to oxidative stress in neuronal HT22 cells,” Brain [60] N. Sahara, M. Murayama, B. Lee et al., “Active c-jun Research, vol. 1005, no. 1-2, pp. 84–89, 2004. N-terminal kinase induces caspase cleavage of tau and [75] L. Wan, G. Nie, J. Zhang et al., “β-amyloid peptide increases additional phosphorylation by GSK-3β is required for tau levels of iron content and oxidative stress in human cell and aggregation,” European Journal of Neuroscience, vol. 27, no. Caenorhabditis elegans models of Alzheimer disease,” Free 11, pp. 2897–2906, 2008. Radical Biology and Medicine, vol. 50, no. 1, pp. 122–129, [61] M. Goedert, M. G. Spillantini, R. Jakes, D. Rutherford, and 2011. R. A. Crowther, “Multiple isoforms of human microtubule- [76] H. M. Abdul, V. Calabrese, M. Calvani, and D. A. Butterfield, associated protein tau: sequences and localization in neu- “Acetyl-L-carnitine-induced up-regulation of heat shock rofibrillary tangles of Alzheimer’s disease,” Neuron,vol. 3,no. proteins protects cortical neurons against amyloid-beta 4, pp. 519–526, 1989. peptide 1-42-mediated oxidative stress and neurotoxicity: [62] M. Tajes, J. Gutierrez-Cuesta, J. Folch et al., “Lithium treat- implications for Alzheimer’s disease,” Journal of Neuroscience ment decreases activities of tau kinases in a murine model Research, vol. 84, no. 2, pp. 398–408, 2006. of senescence,” Journal of Neuropathology and Experimental [77] S. H. Koh, Y. B. Lee, K. S. Kim et al., “Role of GSK-3β Neurology, vol. 67, no. 6, pp. 612–623, 2008. activity in motor neuronal cell death induced by G93A or [63] M. Per ´ ez, F. Hernand ´ ez, F. Lim, J. D´ıaz-Nido, and J. A4V mutant hSOD1 gene,” European Journal of Neuroscience, Avila, “Chronic lithium treatment decreases mutant tau vol. 22, no. 2, pp. 301–309, 2005. protein aggregation in a transgenic mouse model,” Journal [78] Y. J. Zhang, Y. F. Xu, Y. H.Liu,J.Yin,and J. Z. Wang, of Alzheimer’s Disease, vol. 5, no. 4, pp. 301–308, 2003. “Nitric oxide induces tau hyperphosphorylation via glycogen [64] E. G. de Barreda, M. Pe´rez,P.G.Ramos et al., “Tau- synthase kinase-3β activation,” FEBS Letters, vol. 579, no. 27, knockout mice show reduced GSK3-induced hippocampal pp. 6230–6236, 2005. degeneration and learning deficits,” Neurobiology of Disease, [79] M. Bolos, ´ S. Fernandez, and I. Torres-Aleman, “Oral admin- vol. 37, no. 3, pp. 622–629, 2010. istration of a GSK3 inhibitor increases brain insulin-like [65] F. Hernand ´ ez, M. Pe´rez, J. J. Lucas, A. M. Mata, R. Bhat, and growth factor I levels,” Journal of Biological Chemistry,vol. J. Avila, “Glycogen synthase kinase-3 plays a crucial role in 285, no. 23, pp. 17693–17700, 2010. tau exon 10 splicing and intranuclear distribution of SC35: [80] A. Patapoutian and L. F. Reichardt, “Trk receptors: mediators implications for Alzheimer’s disease,” Journal of Biological of neurotrophin action,” Current Opinion in Neurobiology, Chemistry, vol. 279, no. 5, pp. 3801–3806, 2004. vol. 11, no. 3, pp. 272–280, 2001. [66] G. Lee and S. L. Rook, “Expression of tau protein in [81] G. Gallo, A.F. Ernst,S. C.McLoon, and P. C. Letourneau, non-neuronal cells: microtubule binding and stabilization,” “Transient PKA activity is required for initiation but not JournalofCellScience, vol. 102, no. 2, pp. 227–237, 1992. maintenance of BDNF-mediated protection from nitric [67] J. H. Cho and G. V. W. Johnson, “Glycogen synthase kinase oxide-induced growth-cone collapse,” Journal of Neuro- 3β induces caspase-cleaved tau aggregation in situ,” Journal of science, vol. 22, no. 12, pp. 5016–5023, 2002. Biological Chemistry, vol. 279, no. 52, pp. 54716–54723, 2004. [82] L. Mai, R. S. Jope, and X. Li, “BDNF-mediated signal [68] A. Go´mez-Ramos,X.Abad, M. L. Fanarraga,R. Bhat, J. C. transduction is modulated by GSK3β and mood stabilizing Zabala, and J. Avila, “Expression of an altered form of tau in agents,” Journal of Neurochemistry, vol. 82, no. 1, pp. 75–83, Sf9 insect cells results in the assembly of polymers resembling 2002. Alzheimer’s paired helical filaments,” Brain Research,vol. [83] H. S. Phillips, J. M. Hains, M. Armanini, G. R. Laramee, S. 1007, no. 1-2, pp. 57–64, 2004. A. Johnson, and J. W. Winslow, “BDNF mRNA is decreased [69] H. L. Li, H. H. Wang, S. J. Liu et al., “Phosphorylation of tau in the hippocampus of individuals with Alzheimer’s disease,” antagonizes apoptosis by stabilizing β-catenin, a mechanism Neuron, vol. 7, no. 5, pp. 695–702, 1991. 10 International Journal of Alzheimer’s Disease [84] M. G. Murer, Q. Yan, and R. Raisman-Vozari, “Brain-derived element binding protein in the hippocampus of dementia of neurotrophic factor in the control human brain, and in the Alzheimer type,” Brain Research, vol. 824, no. 2, pp. 300– Alzheimer’s disease and Parkinson’s disease,” Progress in 303, 1999. Neurobiology, vol. 63, no. 1, pp. 71–124, 2001. [99] F. Gotsc ¨ hel, C. Kern, S. Lang et al., “Inhibition of GSK3 [85] E. Elliott, R. Atlas, A. Lange, and I. Ginzburg, “Brain-derived differentially modulates NF-κB, CREB, AP-1 and β-catenin neurotrophic factor induces a rapid dephosphorylation of signaling in hepatocytes, but fails to promote TNF-α-induced tau protein through a PI-3Kinase signalling mechanism,” apoptosis,” Experimental Cell Research, vol. 314, no. 6, pp. European Journal of Neuroscience, vol. 22, no. 5, pp. 1081– 1351–1366, 2008. 1089, 2005. [100] M. Per ´ ez, A. I. Rojo, F. Wandosell, J. D´ıaz-Nido, and J. [86] M. Hetman, J. E. Cavanaugh, D. Kimelman, and X. Zhengui, Avila, “Prion peptide induces neuronal cell death through a “Role of glycogen synthase kinase-3β in neuronal apoptosis pathway involving glycogen synthase kinase 3,” Biochemical induced by trophic withdrawal,” Journal of Neuroscience,vol. Journal, vol. 372, no. 1, pp. 129–136, 2003. 20, no. 7, pp. 2567–2574, 2000. [101] NIH/National Institute of Allergy and Infectious Diseases, [87] K. G. Wolter, YI. T. Hsu, C. L. Smith, A. Nechushtan, XU. G. “New form of prion disease damages brain arteries,” Sci- Xi, and R. J. Youle, “Movement of Bax from the cytosol to enceDaily, 2010. mitochondria during apoptosis,” Journalof CellBiology,vol. [102] R. Puri, T. Suzuki, K. Yamakawa, and S. Ganesh, “Hyperphos- 139, no. 5, pp. 1281–1292, 1997. phorylation and aggregation of Tau in laforin-deficient mice, [88] YI.T. Hsu,K. G.Wolter, and R.J. Youle,“Cytosol-to- an animal model for lafora disease,” Journal of Biological membrane redistribution of Bax and Bcl-X during apopto- Chemistry, vol. 284, no. 34, pp. 22657–22663, 2009. sis,” Proceedings of the National Academy of Sciences of the [103] S. M. De La Monte, Y. K. Sohn, and J. R. Wands, “Correlates United States of America, vol. 94, no. 8, pp. 3668–3672, 1997. of p53- and Fas (CD95)-mediated apoptosis in Alzheimer’s [89] M. Saito, S. J. Korsmeyer, and P. H. Schlesinger, “BAX- disease,” Journal of the Neurological Sciences, vol. 152, no. 1, dependent transport of cytochrome C reconstituted in pure pp. 73–83, 1997. liposomes,” Nature Cell Biology, vol. 2, no. 8, pp. 553–555, [104] K. J. Ivins, P. L. Thornton, T. T. Rohn, and C. W. Cotman, “Neuronal apoptosis induced by β-amyloid is mediated by [90] D. A. Linseman, B.D.Butts, T.A.Precht etal., “Glyco- caspase-8,” Neurobiology of Disease, vol. 6, no. 5, pp. 440–449, gen synthase kinase-3β phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis,” Journal of Neuroscience, vol. 24, no. 44, pp. 9993–10002, 2004. [105] I. Ferrer, B. Puig, J. Krupinski, M. Carmona, and R. Blanco, “Fas and Fas ligand expression in Alzheimer’s disease,” Acta [91] T. C. P. Somervaille, D. C. Linch, and A. Khwaja, “Growth factor withdrawal from primary human erythroid progeni- Neuropathologica, vol. 102, no. 2, pp. 121–131, 2001. tors induces apoptosis through a pathway involving glycogen [106] Y. Morishima, Y. Gotoh, J. Zieg et al., “β-amyloid induces synthase kinase-3 and Bax,” Blood, vol. 98, no. 5, pp. 1374– neuronal apoptosis via a mechanism that involves the c-Jun 1381, 2001. N-terminal kinase pathway and the induction of fas ligand,” [92] U. Maurer,C.Charvet, A.S. Wagman, E. Dejardin, and D. R. Journal of Neuroscience, vol. 21, no. 19, pp. 7551–7560, 2001. Green, “Glycogen synthase kinase-3 regulates mitochondrial [107] G. Cantarella, D. Uberti, T. Carsana, G. Lombardo, R. outer membrane permeabilization and apoptosis by destabi- Bernardini, and M. Memo, “Neutralization of TRAIL death lization of MCL-1,” Molecular Cell, vol. 21, no. 6, pp. 749– pathway protects human neuronal cell line from β-amyloid 760, 2006. toxicity,” Cell Death and Differentiation, vol. 10, no. 1, pp. [93] Q. Ding,X.He, J. M. Hsu etal., “Degradationof Mcl-1 by 134–141, 2003. β-TrCP mediates glycogen synthase kinase 3-induced tumor [108] J. H. Su, A. J. Anderson, D. H. Cribbs et al., “Fas and Fas suppression and chemosensitization,” Molecular and Cellular Ligand are associated with neuritic degeneration in the AD Biology, vol. 27, no. 11, pp. 4006–4017, 2007. brain and participate in β-amyloid-induced neuronal death,” [94] B. Chu, R. Zhong, F. Soncin, M. A. Stevenson, and S. K. Neurobiology of Disease, vol. 12, no. 3, pp. 182–193, 2003. Calderwood, “Transcriptional activity of heat shock factor 1 [109] D. T. Yew, W. Ping Li, and W. K. Liu, “Fas and activated at 37 c is repressed through phosphorylation on two distinct caspase 8 in normal, Alzheimer and multiple infarct brains,” serine residues by glycogen synthase kinase 3α and protein Neuroscience Letters, vol. 367, no. 1, pp. 113–117, 2004. kinases cα and cζ,” Journalof BiologicalChemistry, vol. 273, [110] C. K. Wu, L. Thal, D. Pizzo, L. Hansen, E. Masliah, and no. 29, pp. 18640–18646, 1998. C. Geula, “Apoptotic signals within the basal forebrain [95] I. J. Xavier, P. A. Mercier, C. M. McLoughlin, A. Ali, J. R. cholinergic neurons in Alzheimer’s disease,” Experimental Woodgett, and N. Ovsenek, “Glycogen synthase kinase 3β Neurology, vol. 195, no. 2, pp. 484–496, 2005. negatively regulates both DNA-binding and transcriptional [111] D. Uberti, G. Ferrari-Toninelli, S. A. Bonini et al., “Blockade activities of heat shock factor 1,” Journal of Biological of the tumor necrosis factor-related apoptosis inducing lig- Chemistry, vol. 275, no. 37, pp. 29147–29152, 2000. and death receptor DR5 prevents β-amyloid neurotoxicity,” [96] J. W. Tullai, J. Chen, M. E. Schaffer, E. Kamenetsky, S. Kasif, Neuropsychopharmacology, vol. 32, no. 4, pp. 872–880, 2007. and G. M. Cooper, “Glycogen synthase kinase-3 represses [112] K. P. Hoeflich, J. Luo, E. A. Rubie, M. S. Tsao, OU. Jin, and J. cyclic AMP Response element-binding protein (CREB)- R. Woodgett, “Requirement for glycogen synthase kinase-3β targeted Immediate early genes in quiescent cells,” Journal of in cell survival and NF-κBactivation,” Nature, vol. 406, no. Biological Chemistry, vol. 282, no. 13, pp. 9482–9491, 2007. 6791, pp. 86–90, 2000. [97] A. J. Silva, J. H. Kogan, P. W. Frankland, and S. Kida, “CREB and memory,” Annual Review of Neuroscience,vol.21, pp. [113] M. Sun, L. Song, Y. Li, T. Zhou, and R. S. Jope, “Identification 127–148, 1998. of an antiapoptotic protein complex at death receptors,” Cell [98] M. Yamamoto-Sasaki, H. Ozawa, T. Saito, M. Rosle ¨ r, and P. Death and Differentiation, vol. 15, no. 12, pp. 1887–1900, Riederer, “Impaired phosphorylation of cyclic AMP response 2008. International Journal of Alzheimer’s Disease 11 ´ ´ [114] R. Gomez-Sintes, F. Hernandez, A. Bortolozzi et al., “Neu- ronal apoptosis and reversible motor deficit in dominant- negative GSK-3 conditional transgenic mice,” EMBO Journal, vol. 26, no. 11, pp. 2743–2754, 2007. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal

International Journal of Alzheimer's DiseaseHindawi Publishing Corporation

Published: May 11, 2011

There are no references for this article.