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A Unifying Hypothesis for Familial and Sporadic Alzheimer's Disease

A Unifying Hypothesis for Familial and Sporadic Alzheimer's Disease Hindawi Publishing Corporation International Journal of Alzheimer’s Disease Volume 2012, Article ID 978742, 9 pages doi:10.1155/2012/978742 Research Article A Unifying Hypothesis for Familial and Sporadic Alzheimer’s Disease 1 1, 2, 3 Carole J. Proctor and Douglas A. Gray Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5 Correspondence should be addressed to Carole J. Proctor, carole.proctor@ncl.ac.uk Received 25 July 2011; Revised 4 November 2011; Accepted 4 November 2011 Academic Editor: Lucilla Parnetti Copyright © 2012 C. J. Proctor and D. A. Gray. 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. Alzheimer’s disease (AD) is characterised by the aggregation of two quite different proteins, namely, amyloid-beta (Aβ), which forms extracellular plaques, and tau, the main component of cytoplasmic neurofibrillary tangles. The amyloid hypothesis proposes that Aβ plaques precede tangle formation but there is still much controversy concerning the order of events and the linkage between Aβ and tau alterations is still unknown. Mathematical modelling has become an essential tool for generating and evaluating hypotheses involving complex systems. We have therefore used this approach to discover the most probable pathway linking Aβ and tau. The model supports a complex pathway linking Aβ and tau via GSK3β, p53, and oxidative stress. Importantly, the pathway contains a cycle with multiple points of entry. It is this property of the pathway which enables the model to be consistent with both the amyloid hypothesis for familial AD and a more complex pathway for sporadic forms. 1. Introduction been proposed as the upstream driver of both Aβ and tau aggregates. One important candidate is glycogen synthase Alzheimer’s disease (AD) is characterised by the presence kinase-3β (GSK3β). It is well established that GSK3β activity leads to hyperphosphorylation of tau and there is also of extracellular amyloid-beta (Aβ) plaques and cytoplasmic tau tangles and the loss of neurons in specific regions of evidence that it accounts for increased production of Aβ [9]. the brain. The connection between these events is still not Its importance in AD was highlighted in 2008 by the proposal clear although it has been proposed that the formation of of a “GSK3 hypothesis of AD” [10]. Arecentreviewalso plaques precedes the appearance of tangles which in turn surveys data in support of the contention that GSK3β provides the link between Aβ and tau [11]. In addition it has precedes cell death [1, 2]. Confounding the acceptance of such a simple temporal order of events is evidence that been shown that Aβ behaves like an antagonist of insulin plaques are not necessary for disease progression [3]and and prevents activation of Akt [12]. Akt phosphorylates GSK3β which inhibits its activity; Aβ therefore indirectly that the accumulation of plaques can also occur as part of normal ageing with no apparent pathology [4]. Moreover, increases the activity of GSK3β. There is also a link between soluble Aβ may be a better correlate of disease than the p53 and GSK3β and we recently modelled this to show that this interaction might explain the link between protein insoluble plaques [5, 6]. It has recently been suggested that the amyloid hypothesis may only hold for familial forms of aggregation and neuronal loss in AD [13]. The model predicts that GSK3β overactivity leads to an increase in levels the disease but that the situation is much more complex in late-onset forms [7]. It is also possible that Aβ is a damage of Aβ plaques and tau tangles by independent processes response protein [8]. Small and Duff [7]suggest that the supporting the idea of a dual pathway. One way to examine the order of events in disease pathway between Aβ and tau is linear for early-onset AD but hypothesize that a dual pathway links the two in late- pathology is to prevent the formation of plaques and then onset disease [7]. A number of molecular pathways have observe whether or not tau tangles appear. An experimental 2 International Journal of Alzheimer’s Disease Upstream event Upstream Upstream event event Aβ Tau tangles Aβ Tau tangles Aβ Tau tangles Cell Cell Cell death death death (a) (b) (c) Figure 1: Alternative hypotheses for the link between Aβ and tau. (a) Linear pathway. (b) Dual pathway. (c) Complex pathway. procedurefor doing thisisAβ immunization which has been and is then ubiquitinated and targeted for degradation by carried out in many mouse models and also in a number the 26S proteasome. Under normal (unstressed) conditions, of human clinical trials. Many of the mouse models do not both p53 and Mdm2 are kept at low basal levels. However, have tau pathology and so cannot be used to test hypotheses when cells are stressed and DNA damage occurs, p53 is concerning the order of events. In the more relevant 3×Tg- phosphorylated and is then unable to bind to Mdm2 and AD mouse model, experiments indicated that reducing so is no longer degraded. Therefore p53 levels increase. In plaques also led to the clearance of early tau pathology [14]. addition, phosphorylation of p53 increases its activity. Full On the other hand human clinical trials have not shown details of this module are already published [16]. Under any clear evidence of a reduction in tau tangles in regions normal conditions when p53 levels are low, it is unable to where plaques were reduced [15]. Our model of GSK3/p53 bind to GSK3β and so we assume that GSK3β activity is low [13] can examine the effect of increased clearance of Aβ by when cells are not stressed. the simple modification of increasing the rate of Aβ (soluble The model also includes reactions for the production, form) removal. By doing so it is possible to test whether there clearance and aggregation of Aβ, and the phosphoryla- is a linear or a dual pathway. If the pathway is linear, then the tion/dephosphorylation and aggregation of tau. In addition model should predict that increasing clearance of Aβ will also we assume that Aβ results in increased generation of ROS reduce the formation of tau tangles (Figure 1(a)). If there is and increased transcription of p53. The full details of a dual pathway, then increasing the clearance of Aβ will not the model are available in an open access journal and affect the levels of tau tangles (Figure 1(b)). However, there the SBML code is available from Biomodels (BioModels is a third possibility (complex pathway): Aβ may not directly ID:BIOMD0000000286)[18]. The simulations were carried affect the formation of tau tangles in a linear pathway but out using the Gillespie algorithm on the Biology of Ageing may still have indirect effects (Figure 1(c)). e-Science Integration and Simulation (BASIS) system [19– 21]. The model results were analysed and plotted using the R package. 2. Methods We previously built a stochastic dynamic model of p53 reg- 3. Results ulation [16] which was then extended to include GSK3β,Aβ and tau [13]. The models are encoded in the Systems Biology 3.1. Increased Aβ Clearance from Day 0. In our previous Markup Language (SBML), a computer-readable format for model we set the rates for aggregation of tau and Aβ at levels network models [17]. SBML allows models to be easily so that if there was an increase in tau phosphorylation or modified and extended and also enables sharing of models an increase in Aβ production, the formation of aggregates since the code is publicly available from the Biomodels would appear within 2 or 3 days. In reality, the aggregation database [18]. The extended GSK3 model includes a module processislikelytohavemuchlongerlag periods. Acceleration for the DNA damage response which leads to elevated levels of the aggregation process in our computer model is merely of p53, which can then bind to GSK3β. We assume that a device to increase the throughput of simulations. With binding of GSK3β to p53 increased the activity of both normal rates of Aβ clearance, our model predicts that a small proteins. The model includes a module for p53 turnover percentage of cells do not accumulate any plaques or tangles in which we assume that p53 binds to the E3 ligase Mdm2 by 12 days (Figures 2(c) and 2(f)). However, the majority International Journal of Alzheimer’s Disease 3 800 800 600 600 0 0 02468 10 12 024 6 8 10 12 024 6 8 10 12 p53 p53 p53 (a) (b) (c) 150 150 50 50 02468 10 12 024 6 8 10 12 024 68 10 12 Time (days) Time (days) Time (days) Gsk3b p53 Gsk3b p53 Gsk3b p53 Tau tangles Tau tangles Tau tangles Aβ plaques damDNA Aβ plaques damDNA Aβ plaques damDNA (d) (e) (f) Figure 2: Simulation output for model with high aggregation rates and normal Aβ clearance. Three different individual simulations are shown. The plots in each column are from the same simulation. (a)–(c) Levels of p53 (total pool including bound and ubiquitinated species). (e,f) p53 bound to GSK3β (GSK3b p53), damaged DNA (damDNA), tau tangles, and Aβ plaques are shown. of simulated cells accumulate both plaques and tangles due or tangles and p53 levels remain low over a simulated 12-day to stochastic DNA damage which leads to increased levels period (Figure 3,green curveand Figure 4(a)). This supports and activation of p53 (Figures 2(a), 2(b), 2(d) and 2(e)). The the hypothesis that the increase in ROS via Aβ reinforces the model predicts that as a result of p53 activation, GSK3β activ- cycle by activation of p53 and GSK3β as suggested above. ity increases resulting in increased phosphorylation of tau and formation of tau tangles. In addition, increased p53 and 3.2. Effect of Increasing Aβ Clearance at Different Time GSK3β activity result in increased production of Aβ which Points. It is of interest to examine the effect of increasing then aggregates to form plaques. Interestingly, the model Aβ clearance at later timepoints, since such interventions predicts that tau tangles precede Aβ plaques suggesting that may occur after soluble Aβ or even plaques have had time plaques and tangles are formed independently. The increase to form. Studies on Aβ immunization in mice indicate in Aβ also leads to more ROS and further DNA damage that interventions are more effective if administered early, which in turn leads to further activation of p53 and a cycle suggesting that the load of Aβ at the time of immunization ensues. Increasing the clearance rate of Aβ, by two orders of is important [22]. We therefore used the model to explore magnitude, at day 0 prevents any accumulation of plaques the effect of increasing the clearance of Aβ at different Number of molecules Number of molecules 4 International Journal of Alzheimer’s Disease we ran 100 simulations in the model with increased Aβ clearance at day 8 and blocked the production of ROS via Aβ (by setting the parameter for Aβ-mediated ROS production to zero). Figure 5(a) shows the mean value of these simulations for p53, GSK3β bound to p53, Aβ plaques, tau tangles, and damaged DNA over a 12-day period. It can be seen that with the exception of p53, the levels of the all species shown are close to zero. So the model predicts that this intervention completely prevents the increase in DNA damage, the elevation of p53, the increase in GSK3β activity, and the formation of plaques and tangles producing results similar to increased clearance of Aβ at day 0 (see Figure 4(a)). 3.4. Inhibition of GSK3β/p53 Binding. To examine the effect of GSK3β/p53 binding on the aggregation process we 02468 10 12 inhibited the interaction between GSK3β and p53 (by setting Time (days) the parameter for GSK3β/p53 binding to zero). We ran 100 simulations with increased clearance of Aβ on day 8 (with No intervention Day 4 ROS production via Aβ restored). This additional interven- Day 8 Day 2 tion also prevented the formation of plaques and tangles even Day 6 Day 0 though p53 levels rose during the simulation (Figure 5(b)). Figure 3: Levels of p53 under conditions of high aggregation rates Therefore the model predicts that Aβ clearanceatlatetime and increased Aβ clearance at different time points. Each line points may be beneficial if additional interventions are used shows the mean levels of p53 (total pool including bound and such as simultaneously reducing ROS levels or preventing the ubiquitinated species) from 100 simulations over a 12-day period. activation of GSK3β. time points (Figures 3 and 4). This was done by adding a 3.5. Effect of Aβ Immunization on Neuronal Loss. Cell death timed event to the SBML code so that the parameter for Aβ is not currently explicitly included in the model, but we can clearance is reduced by two orders of magnitude at time 2, assume that if p53 reaches a threshold then it triggers an 4, 6, or 8 days from the start of the simulation. The model apoptotic pathway. Since it would be unrealistic to assign to predicts that increasing Aβ clearance at early time points (up the threshold an exact and invariable value, the threshold to day 4) leads to a much lower level of Aβ so that no plaques level of p53 is chosen from a random distribution (normal form and there are also much lower levels of tau tangles and distribution, mean 600, variance 50) for each simulation run. p53 (Figures 3, 4(a)–4(c)). Note that the intervention at day For each simulation the level of p53 was tracked over time, 2leads to lowlevelsofAβ monomers which are sufficient starting at time zero. If the level of p53 exceeded the chosen to slightly increase ROS levels (black curve in Figure 4(b)). threshold, the time at which this occurred was recorded and Accordingly p53 levels rise slightly (red line in Figure 3)and the simulated cell was considered to have undergone cell the activity of GSK3β is increased leading to an increase in deathatthistime. Thepercentageofviablecells at each time phosphorylation and aggregation of tau (Figure 4(b)). Inter- point was calculated for each of the intervention times and ventions at later time points (day 6 or later) result in lower plotted (Figure 6). The model predicts that there are no cell levels of plaques compared to normal Aβ clearance (compare deaths if Aβ clearance is increased at early time points but light blue curves in Figures 4(d) and 4(e) with 4(f)) but the as the intervention is increasingly delayed the percentage of levels of tau tangles are not significantly lower compared to cell death increases. If the intervention is as late as day 8, no intervention (Figures 4(d)–4(f), dark blue curves). This there is little improvement in cell viability compared to no is due to the formation of Aβ monomers and oligomers intervention. The model therefore indicates that increased occurring before the intervention, which leads to increases clearance of Aβ needs to occur at early time points before in ROS, activation of GSK3β, and increased phosphorylation there is any accumulation of Aβ. of tau which is then more likely to form tangles. Figure 3 shows p53 levels start to increase after day 2 and continue 4. Discussion to increase until the intervention of increased Aβ clearance occurs. This can be seen clearly by the fact that all curves The model shows that reducing the burden of Aβ reduces are initially close together but as the intervention occurs, p53 levels of ROS, which leads to less DNA damage, lower p53 levels stabilise. The model therefore suggests that even a low activity, lower GSK3β activity, and reduced tau phosphory- level of soluble Aβ monomers and oligomers is sufficient to lation. If Aβ clearance is increased at early time points, there trigger an increase in ROS, which leads to an increase in p53. is a decrease in plaques and also a reduction in tau tangles. The model therefore does not support a dual pathway 3.3. Inhibition of ROS Production via Aβ. To confirm whether (Figure 1(b)). On the other hand, increasing Aβ clearance at the increase in p53 is due to Aβ-mediated ROS production, late time points reduced plaque formation but did not reduce Number of molecules International Journal of Alzheimer’s Disease 5 100 100 100 80 80 60 60 40 40 20 20 20 0 0 0 2 4 6 8 10 12 02468 10 12 02468 10 12 Gsk3b p53 Tau tangles Gsk3b p53 Tau tangles Gsk3b p53 Tau tangles Aβ plaques damDNA Aβ plaques damDNA Aβ plaques damDNA Aβ oligomers Aβ monomers Aβ oligomers Aβ monomers Aβ oligomers Aβ monomers ROS ROS ROS (a) (b) (c) 100 100 80 80 60 60 20 20 0 0 02468 10 12 02468 10 12 0 2 4 6 8 10 12 Time (days) Time (days) Time (days) Gsk3b p53 Tau tangles Gsk3b p53 Tau tangles Gsk3b p53 Tau tangles Aβ plaques damDNA Aβ plaques damDNA Aβ plaques damDNA Aβ oligomers Aβ monomers Aβ oligomers Aβ monomers Aβ oligomers Aβ monomers ROS ROS ROS (d) (e) (f) Figure 4: Simulation results for model with high aggregation rates and increased Aβ clearance at different time points. Each graph shows the mean of 100 simulations. The clearance rate of Aβ was increased at the following time points: (a) Day 0, (b) Day 2, (c) Day 4, (d) Day 6, (e) Day 8, (f) No intervention. p53 bound to GSK3β (GSK3b p53), damaged DNA (damDNA), ROS, tau tangles and Aβ monomers, oligomers and plaques, are shown. tangle formation. Neither then does the model support a propose a new hypothesis in which the pathway between Aβ linear pathway (Figure 1(a)). Rather the model supports and tau is via ROS, p53, and GSK3β (Figure 7). It is impor- the complex pathway where plaques and tangles can form tant to note that GSK3β, which is shown at the top of the independently due to an upstream event but with increased diagram, is not necessarily the starting point for the ensuing tangle formation in the presence of Aβ (Figure 1(c)). We cascade of events. For example, the initiating event could Number of molecules Number of molecules 6 International Journal of Alzheimer’s Disease 02468 10 12 02468 10 12 Time (days) Time (days) p53 p53 Tau tangles Tau tangles damDNA Gsk3b p53 Gsk3b p53 damDNA Aβ plaques Aβ plaques (a) (b) Figure 5: Increased Aβ clearance on day 8 with additional interventions. Each graph shows the mean of 100 simulations. (a) Blockage of ROS production via Aβ (parameter for Aβ-mediated ROS production set to zero). (b) Inhibition of GSK3β/p53 binding (parameter for GSK3β/p53 binding set to zero). Note that apart from p53, all proteins shown in the graphs have levels close to zero and so not all the lines can be seen. 02468 10 12 Time (days) Day 0 Day 6 Day 2 Day 8 Day 4 No intervention Figure 6: Percentage of viable simulated cells for increased Aβ clearance at different time points. Each curve shows how the percentage of viable cells (from 100 simulations) changes with time over a 12-day period when Aβ clearance is increased at days 0, 2, 4, 6, or 8 and for the normal clearance rate (no intervention). Number of molecules Percentage of viable cells International Journal of Alzheimer’s Disease 7 GSK3β Aβ Stress ROS Tau tangles p53 Cell death Figure 7: New hypotheses of AD involving GSK3 and p53. Our model supports that the pathway between Aβ and tau is via ROS, p53, and GSK3β. Note that there is a cycle in the diagram between GSK3β,Aβ, ROS, and p53 which can start at any point. Full details are in the text. be an increase in soluble Aβ which then leads to plaques There is experimental data to support all the arrows in and an increase in ROS. Elevated ROS may then cause DNA the diagram, however the importance of p53 in the loop damage which results in increased levels of p53, followed by has not been fully investigated. Although it is known that increased activity of GSK3β. Finally the increased activity p53 increases the activity of GSK3β [23] and that increased of GSK3β leads to tau hyperphosphorylation and tangle p53 activity indirectly leads to tau hyperphosphorylation formation. In addition, levels of Aβ are increased and so there [24], as yet no experiments have been carried out to prove is a positive feedback loop which reinforces the cycle on the that the link between p53 and tau is GSK3β as our model left. Note that GSK3β also increases p53 activity providing suggests. This prediction could be tested experimentally by an additional positive feedback in the cycle. The cycle could either inhibiting or overexpressing p53 in cells expressing Aβ also begin with increased ROS due to cellular stress, an and then measuring GSK3β activity and levels of phospho- increase in dysfunctional mitochondria, and/or a decline in tau. the efficiency of the antioxidant system. Furthermore, the The model is a simplification of the system but as the cycle could begin with p53 due to stress-induced DNA dam- model is encoded in SBML, it can easily be extended to age, telomere uncapping, or inhibition of the proteasome. include further details. Other important components which Whatever the initiating event the positive feedback loops could be added are chaperones (GSK3β is a client of Hsp90), could promote a self-perpetuating and amplifying cascade of more detail of tau regulation, the insulin pathway, and wnt events that could lead to frank AD. signalling pathways. It would be of particular interest to The model also supports the amyloid hypothesis for include the insulin signalling pathway in order to explore the familial forms of the disease, since the initiating event for connection between AD and type 2 diabetes since GSK3β has this form of the disease would be increased production of been implicated in both diseases. Mitochondria also play an Aβ due to mutations in genes involved in APP processing. In important role in the disease process. For example, damaged this case the cycle starts with Aβ and then leads to increased mitochondria may accumulate in postmitotic neurons and ROS, DNA damage, increased levels of p53, increased cause an increase in ROS which could start the vicious GSK3β activity, and finally hyperphosphorylation of tau and cycle shown in Figure 7. In addition, soluble Aβ binds to formation of tangles in a seemingly linear pathway. The Aβ-binding alcohol dehydrogenase (ABAD) which leads to model also explains why tau pathology may be seen before increase ROS via mitochondrial dysfunction [25, 26]. Recent plaques or even without plaques if the initiating event is data show that truncated tau and Aβ act cooperatively to increased activity of GSK3β, or if the cycle starts with ROS impair mitochondrial function and reduce mitochondrial or p53. The scenario in which tangles appear without any transport in neurons [27]. A model of mitochondrial plaques would suggest however that there must also be more dynamics is currently being developed and linking this with efficient clearance of Aβ since an increase in GSK3β activity the current model will give a more complete picture of the also increases Aβ production. disease process. 8 International Journal of Alzheimer’s Disease Aβ immunotherapy works by either active immuniza- [7] S.A.Small andK.Duff, “Linking Aβ and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis,” Neuron, vol. tion with Aβ aggregates or by passive transfer of anti- 60, no. 4, pp. 534–542, 2008. Aβ antibodies. Both approaches have been shown to pre- [8] J. 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A Unifying Hypothesis for Familial and Sporadic Alzheimer's Disease

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Copyright © 2012 Carole J. Proctor and Douglas A. Gray. 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.
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Abstract

Hindawi Publishing Corporation International Journal of Alzheimer’s Disease Volume 2012, Article ID 978742, 9 pages doi:10.1155/2012/978742 Research Article A Unifying Hypothesis for Familial and Sporadic Alzheimer’s Disease 1 1, 2, 3 Carole J. Proctor and Douglas A. Gray Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5 Correspondence should be addressed to Carole J. Proctor, carole.proctor@ncl.ac.uk Received 25 July 2011; Revised 4 November 2011; Accepted 4 November 2011 Academic Editor: Lucilla Parnetti Copyright © 2012 C. J. Proctor and D. A. Gray. 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. Alzheimer’s disease (AD) is characterised by the aggregation of two quite different proteins, namely, amyloid-beta (Aβ), which forms extracellular plaques, and tau, the main component of cytoplasmic neurofibrillary tangles. The amyloid hypothesis proposes that Aβ plaques precede tangle formation but there is still much controversy concerning the order of events and the linkage between Aβ and tau alterations is still unknown. Mathematical modelling has become an essential tool for generating and evaluating hypotheses involving complex systems. We have therefore used this approach to discover the most probable pathway linking Aβ and tau. The model supports a complex pathway linking Aβ and tau via GSK3β, p53, and oxidative stress. Importantly, the pathway contains a cycle with multiple points of entry. It is this property of the pathway which enables the model to be consistent with both the amyloid hypothesis for familial AD and a more complex pathway for sporadic forms. 1. Introduction been proposed as the upstream driver of both Aβ and tau aggregates. One important candidate is glycogen synthase Alzheimer’s disease (AD) is characterised by the presence kinase-3β (GSK3β). It is well established that GSK3β activity leads to hyperphosphorylation of tau and there is also of extracellular amyloid-beta (Aβ) plaques and cytoplasmic tau tangles and the loss of neurons in specific regions of evidence that it accounts for increased production of Aβ [9]. the brain. The connection between these events is still not Its importance in AD was highlighted in 2008 by the proposal clear although it has been proposed that the formation of of a “GSK3 hypothesis of AD” [10]. Arecentreviewalso plaques precedes the appearance of tangles which in turn surveys data in support of the contention that GSK3β provides the link between Aβ and tau [11]. In addition it has precedes cell death [1, 2]. Confounding the acceptance of such a simple temporal order of events is evidence that been shown that Aβ behaves like an antagonist of insulin plaques are not necessary for disease progression [3]and and prevents activation of Akt [12]. Akt phosphorylates GSK3β which inhibits its activity; Aβ therefore indirectly that the accumulation of plaques can also occur as part of normal ageing with no apparent pathology [4]. Moreover, increases the activity of GSK3β. There is also a link between soluble Aβ may be a better correlate of disease than the p53 and GSK3β and we recently modelled this to show that this interaction might explain the link between protein insoluble plaques [5, 6]. It has recently been suggested that the amyloid hypothesis may only hold for familial forms of aggregation and neuronal loss in AD [13]. The model predicts that GSK3β overactivity leads to an increase in levels the disease but that the situation is much more complex in late-onset forms [7]. It is also possible that Aβ is a damage of Aβ plaques and tau tangles by independent processes response protein [8]. Small and Duff [7]suggest that the supporting the idea of a dual pathway. One way to examine the order of events in disease pathway between Aβ and tau is linear for early-onset AD but hypothesize that a dual pathway links the two in late- pathology is to prevent the formation of plaques and then onset disease [7]. A number of molecular pathways have observe whether or not tau tangles appear. An experimental 2 International Journal of Alzheimer’s Disease Upstream event Upstream Upstream event event Aβ Tau tangles Aβ Tau tangles Aβ Tau tangles Cell Cell Cell death death death (a) (b) (c) Figure 1: Alternative hypotheses for the link between Aβ and tau. (a) Linear pathway. (b) Dual pathway. (c) Complex pathway. procedurefor doing thisisAβ immunization which has been and is then ubiquitinated and targeted for degradation by carried out in many mouse models and also in a number the 26S proteasome. Under normal (unstressed) conditions, of human clinical trials. Many of the mouse models do not both p53 and Mdm2 are kept at low basal levels. However, have tau pathology and so cannot be used to test hypotheses when cells are stressed and DNA damage occurs, p53 is concerning the order of events. In the more relevant 3×Tg- phosphorylated and is then unable to bind to Mdm2 and AD mouse model, experiments indicated that reducing so is no longer degraded. Therefore p53 levels increase. In plaques also led to the clearance of early tau pathology [14]. addition, phosphorylation of p53 increases its activity. Full On the other hand human clinical trials have not shown details of this module are already published [16]. Under any clear evidence of a reduction in tau tangles in regions normal conditions when p53 levels are low, it is unable to where plaques were reduced [15]. Our model of GSK3/p53 bind to GSK3β and so we assume that GSK3β activity is low [13] can examine the effect of increased clearance of Aβ by when cells are not stressed. the simple modification of increasing the rate of Aβ (soluble The model also includes reactions for the production, form) removal. By doing so it is possible to test whether there clearance and aggregation of Aβ, and the phosphoryla- is a linear or a dual pathway. If the pathway is linear, then the tion/dephosphorylation and aggregation of tau. In addition model should predict that increasing clearance of Aβ will also we assume that Aβ results in increased generation of ROS reduce the formation of tau tangles (Figure 1(a)). If there is and increased transcription of p53. The full details of a dual pathway, then increasing the clearance of Aβ will not the model are available in an open access journal and affect the levels of tau tangles (Figure 1(b)). However, there the SBML code is available from Biomodels (BioModels is a third possibility (complex pathway): Aβ may not directly ID:BIOMD0000000286)[18]. The simulations were carried affect the formation of tau tangles in a linear pathway but out using the Gillespie algorithm on the Biology of Ageing may still have indirect effects (Figure 1(c)). e-Science Integration and Simulation (BASIS) system [19– 21]. The model results were analysed and plotted using the R package. 2. Methods We previously built a stochastic dynamic model of p53 reg- 3. Results ulation [16] which was then extended to include GSK3β,Aβ and tau [13]. The models are encoded in the Systems Biology 3.1. Increased Aβ Clearance from Day 0. In our previous Markup Language (SBML), a computer-readable format for model we set the rates for aggregation of tau and Aβ at levels network models [17]. SBML allows models to be easily so that if there was an increase in tau phosphorylation or modified and extended and also enables sharing of models an increase in Aβ production, the formation of aggregates since the code is publicly available from the Biomodels would appear within 2 or 3 days. In reality, the aggregation database [18]. The extended GSK3 model includes a module processislikelytohavemuchlongerlag periods. Acceleration for the DNA damage response which leads to elevated levels of the aggregation process in our computer model is merely of p53, which can then bind to GSK3β. We assume that a device to increase the throughput of simulations. With binding of GSK3β to p53 increased the activity of both normal rates of Aβ clearance, our model predicts that a small proteins. The model includes a module for p53 turnover percentage of cells do not accumulate any plaques or tangles in which we assume that p53 binds to the E3 ligase Mdm2 by 12 days (Figures 2(c) and 2(f)). However, the majority International Journal of Alzheimer’s Disease 3 800 800 600 600 0 0 02468 10 12 024 6 8 10 12 024 6 8 10 12 p53 p53 p53 (a) (b) (c) 150 150 50 50 02468 10 12 024 6 8 10 12 024 68 10 12 Time (days) Time (days) Time (days) Gsk3b p53 Gsk3b p53 Gsk3b p53 Tau tangles Tau tangles Tau tangles Aβ plaques damDNA Aβ plaques damDNA Aβ plaques damDNA (d) (e) (f) Figure 2: Simulation output for model with high aggregation rates and normal Aβ clearance. Three different individual simulations are shown. The plots in each column are from the same simulation. (a)–(c) Levels of p53 (total pool including bound and ubiquitinated species). (e,f) p53 bound to GSK3β (GSK3b p53), damaged DNA (damDNA), tau tangles, and Aβ plaques are shown. of simulated cells accumulate both plaques and tangles due or tangles and p53 levels remain low over a simulated 12-day to stochastic DNA damage which leads to increased levels period (Figure 3,green curveand Figure 4(a)). This supports and activation of p53 (Figures 2(a), 2(b), 2(d) and 2(e)). The the hypothesis that the increase in ROS via Aβ reinforces the model predicts that as a result of p53 activation, GSK3β activ- cycle by activation of p53 and GSK3β as suggested above. ity increases resulting in increased phosphorylation of tau and formation of tau tangles. In addition, increased p53 and 3.2. Effect of Increasing Aβ Clearance at Different Time GSK3β activity result in increased production of Aβ which Points. It is of interest to examine the effect of increasing then aggregates to form plaques. Interestingly, the model Aβ clearance at later timepoints, since such interventions predicts that tau tangles precede Aβ plaques suggesting that may occur after soluble Aβ or even plaques have had time plaques and tangles are formed independently. The increase to form. Studies on Aβ immunization in mice indicate in Aβ also leads to more ROS and further DNA damage that interventions are more effective if administered early, which in turn leads to further activation of p53 and a cycle suggesting that the load of Aβ at the time of immunization ensues. Increasing the clearance rate of Aβ, by two orders of is important [22]. We therefore used the model to explore magnitude, at day 0 prevents any accumulation of plaques the effect of increasing the clearance of Aβ at different Number of molecules Number of molecules 4 International Journal of Alzheimer’s Disease we ran 100 simulations in the model with increased Aβ clearance at day 8 and blocked the production of ROS via Aβ (by setting the parameter for Aβ-mediated ROS production to zero). Figure 5(a) shows the mean value of these simulations for p53, GSK3β bound to p53, Aβ plaques, tau tangles, and damaged DNA over a 12-day period. It can be seen that with the exception of p53, the levels of the all species shown are close to zero. So the model predicts that this intervention completely prevents the increase in DNA damage, the elevation of p53, the increase in GSK3β activity, and the formation of plaques and tangles producing results similar to increased clearance of Aβ at day 0 (see Figure 4(a)). 3.4. Inhibition of GSK3β/p53 Binding. To examine the effect of GSK3β/p53 binding on the aggregation process we 02468 10 12 inhibited the interaction between GSK3β and p53 (by setting Time (days) the parameter for GSK3β/p53 binding to zero). We ran 100 simulations with increased clearance of Aβ on day 8 (with No intervention Day 4 ROS production via Aβ restored). This additional interven- Day 8 Day 2 tion also prevented the formation of plaques and tangles even Day 6 Day 0 though p53 levels rose during the simulation (Figure 5(b)). Figure 3: Levels of p53 under conditions of high aggregation rates Therefore the model predicts that Aβ clearanceatlatetime and increased Aβ clearance at different time points. Each line points may be beneficial if additional interventions are used shows the mean levels of p53 (total pool including bound and such as simultaneously reducing ROS levels or preventing the ubiquitinated species) from 100 simulations over a 12-day period. activation of GSK3β. time points (Figures 3 and 4). This was done by adding a 3.5. Effect of Aβ Immunization on Neuronal Loss. Cell death timed event to the SBML code so that the parameter for Aβ is not currently explicitly included in the model, but we can clearance is reduced by two orders of magnitude at time 2, assume that if p53 reaches a threshold then it triggers an 4, 6, or 8 days from the start of the simulation. The model apoptotic pathway. Since it would be unrealistic to assign to predicts that increasing Aβ clearance at early time points (up the threshold an exact and invariable value, the threshold to day 4) leads to a much lower level of Aβ so that no plaques level of p53 is chosen from a random distribution (normal form and there are also much lower levels of tau tangles and distribution, mean 600, variance 50) for each simulation run. p53 (Figures 3, 4(a)–4(c)). Note that the intervention at day For each simulation the level of p53 was tracked over time, 2leads to lowlevelsofAβ monomers which are sufficient starting at time zero. If the level of p53 exceeded the chosen to slightly increase ROS levels (black curve in Figure 4(b)). threshold, the time at which this occurred was recorded and Accordingly p53 levels rise slightly (red line in Figure 3)and the simulated cell was considered to have undergone cell the activity of GSK3β is increased leading to an increase in deathatthistime. Thepercentageofviablecells at each time phosphorylation and aggregation of tau (Figure 4(b)). Inter- point was calculated for each of the intervention times and ventions at later time points (day 6 or later) result in lower plotted (Figure 6). The model predicts that there are no cell levels of plaques compared to normal Aβ clearance (compare deaths if Aβ clearance is increased at early time points but light blue curves in Figures 4(d) and 4(e) with 4(f)) but the as the intervention is increasingly delayed the percentage of levels of tau tangles are not significantly lower compared to cell death increases. If the intervention is as late as day 8, no intervention (Figures 4(d)–4(f), dark blue curves). This there is little improvement in cell viability compared to no is due to the formation of Aβ monomers and oligomers intervention. The model therefore indicates that increased occurring before the intervention, which leads to increases clearance of Aβ needs to occur at early time points before in ROS, activation of GSK3β, and increased phosphorylation there is any accumulation of Aβ. of tau which is then more likely to form tangles. Figure 3 shows p53 levels start to increase after day 2 and continue 4. Discussion to increase until the intervention of increased Aβ clearance occurs. This can be seen clearly by the fact that all curves The model shows that reducing the burden of Aβ reduces are initially close together but as the intervention occurs, p53 levels of ROS, which leads to less DNA damage, lower p53 levels stabilise. The model therefore suggests that even a low activity, lower GSK3β activity, and reduced tau phosphory- level of soluble Aβ monomers and oligomers is sufficient to lation. If Aβ clearance is increased at early time points, there trigger an increase in ROS, which leads to an increase in p53. is a decrease in plaques and also a reduction in tau tangles. The model therefore does not support a dual pathway 3.3. Inhibition of ROS Production via Aβ. To confirm whether (Figure 1(b)). On the other hand, increasing Aβ clearance at the increase in p53 is due to Aβ-mediated ROS production, late time points reduced plaque formation but did not reduce Number of molecules International Journal of Alzheimer’s Disease 5 100 100 100 80 80 60 60 40 40 20 20 20 0 0 0 2 4 6 8 10 12 02468 10 12 02468 10 12 Gsk3b p53 Tau tangles Gsk3b p53 Tau tangles Gsk3b p53 Tau tangles Aβ plaques damDNA Aβ plaques damDNA Aβ plaques damDNA Aβ oligomers Aβ monomers Aβ oligomers Aβ monomers Aβ oligomers Aβ monomers ROS ROS ROS (a) (b) (c) 100 100 80 80 60 60 20 20 0 0 02468 10 12 02468 10 12 0 2 4 6 8 10 12 Time (days) Time (days) Time (days) Gsk3b p53 Tau tangles Gsk3b p53 Tau tangles Gsk3b p53 Tau tangles Aβ plaques damDNA Aβ plaques damDNA Aβ plaques damDNA Aβ oligomers Aβ monomers Aβ oligomers Aβ monomers Aβ oligomers Aβ monomers ROS ROS ROS (d) (e) (f) Figure 4: Simulation results for model with high aggregation rates and increased Aβ clearance at different time points. Each graph shows the mean of 100 simulations. The clearance rate of Aβ was increased at the following time points: (a) Day 0, (b) Day 2, (c) Day 4, (d) Day 6, (e) Day 8, (f) No intervention. p53 bound to GSK3β (GSK3b p53), damaged DNA (damDNA), ROS, tau tangles and Aβ monomers, oligomers and plaques, are shown. tangle formation. Neither then does the model support a propose a new hypothesis in which the pathway between Aβ linear pathway (Figure 1(a)). Rather the model supports and tau is via ROS, p53, and GSK3β (Figure 7). It is impor- the complex pathway where plaques and tangles can form tant to note that GSK3β, which is shown at the top of the independently due to an upstream event but with increased diagram, is not necessarily the starting point for the ensuing tangle formation in the presence of Aβ (Figure 1(c)). We cascade of events. For example, the initiating event could Number of molecules Number of molecules 6 International Journal of Alzheimer’s Disease 02468 10 12 02468 10 12 Time (days) Time (days) p53 p53 Tau tangles Tau tangles damDNA Gsk3b p53 Gsk3b p53 damDNA Aβ plaques Aβ plaques (a) (b) Figure 5: Increased Aβ clearance on day 8 with additional interventions. Each graph shows the mean of 100 simulations. (a) Blockage of ROS production via Aβ (parameter for Aβ-mediated ROS production set to zero). (b) Inhibition of GSK3β/p53 binding (parameter for GSK3β/p53 binding set to zero). Note that apart from p53, all proteins shown in the graphs have levels close to zero and so not all the lines can be seen. 02468 10 12 Time (days) Day 0 Day 6 Day 2 Day 8 Day 4 No intervention Figure 6: Percentage of viable simulated cells for increased Aβ clearance at different time points. Each curve shows how the percentage of viable cells (from 100 simulations) changes with time over a 12-day period when Aβ clearance is increased at days 0, 2, 4, 6, or 8 and for the normal clearance rate (no intervention). Number of molecules Percentage of viable cells International Journal of Alzheimer’s Disease 7 GSK3β Aβ Stress ROS Tau tangles p53 Cell death Figure 7: New hypotheses of AD involving GSK3 and p53. Our model supports that the pathway between Aβ and tau is via ROS, p53, and GSK3β. Note that there is a cycle in the diagram between GSK3β,Aβ, ROS, and p53 which can start at any point. Full details are in the text. be an increase in soluble Aβ which then leads to plaques There is experimental data to support all the arrows in and an increase in ROS. Elevated ROS may then cause DNA the diagram, however the importance of p53 in the loop damage which results in increased levels of p53, followed by has not been fully investigated. Although it is known that increased activity of GSK3β. Finally the increased activity p53 increases the activity of GSK3β [23] and that increased of GSK3β leads to tau hyperphosphorylation and tangle p53 activity indirectly leads to tau hyperphosphorylation formation. In addition, levels of Aβ are increased and so there [24], as yet no experiments have been carried out to prove is a positive feedback loop which reinforces the cycle on the that the link between p53 and tau is GSK3β as our model left. Note that GSK3β also increases p53 activity providing suggests. This prediction could be tested experimentally by an additional positive feedback in the cycle. The cycle could either inhibiting or overexpressing p53 in cells expressing Aβ also begin with increased ROS due to cellular stress, an and then measuring GSK3β activity and levels of phospho- increase in dysfunctional mitochondria, and/or a decline in tau. the efficiency of the antioxidant system. Furthermore, the The model is a simplification of the system but as the cycle could begin with p53 due to stress-induced DNA dam- model is encoded in SBML, it can easily be extended to age, telomere uncapping, or inhibition of the proteasome. include further details. Other important components which Whatever the initiating event the positive feedback loops could be added are chaperones (GSK3β is a client of Hsp90), could promote a self-perpetuating and amplifying cascade of more detail of tau regulation, the insulin pathway, and wnt events that could lead to frank AD. signalling pathways. It would be of particular interest to The model also supports the amyloid hypothesis for include the insulin signalling pathway in order to explore the familial forms of the disease, since the initiating event for connection between AD and type 2 diabetes since GSK3β has this form of the disease would be increased production of been implicated in both diseases. Mitochondria also play an Aβ due to mutations in genes involved in APP processing. In important role in the disease process. For example, damaged this case the cycle starts with Aβ and then leads to increased mitochondria may accumulate in postmitotic neurons and ROS, DNA damage, increased levels of p53, increased cause an increase in ROS which could start the vicious GSK3β activity, and finally hyperphosphorylation of tau and cycle shown in Figure 7. In addition, soluble Aβ binds to formation of tangles in a seemingly linear pathway. The Aβ-binding alcohol dehydrogenase (ABAD) which leads to model also explains why tau pathology may be seen before increase ROS via mitochondrial dysfunction [25, 26]. Recent plaques or even without plaques if the initiating event is data show that truncated tau and Aβ act cooperatively to increased activity of GSK3β, or if the cycle starts with ROS impair mitochondrial function and reduce mitochondrial or p53. 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International Journal of Alzheimer's DiseaseHindawi Publishing Corporation

Published: Feb 14, 2012

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