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Mitochondria Are Related to Synaptic Pathology in Alzheimer's Disease

Mitochondria Are Related to Synaptic Pathology in Alzheimer's Disease SAGE-Hindawi Access to Research International Journal of Alzheimer’s Disease Volume 2011, Article ID 305395, 7 pages doi:10.4061/2011/305395 Clinical Study Mitochondria Are Related to Synaptic Pathology in Alzheimer’s Disease Stavros J. Baloyannis Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, 54006 Thessaloniki, Greece Correspondence should be addressed to Stavros J. Baloyannis, sibh844@otenet.gr Received 6 March 2011; Accepted 12 July 2011 Academic Editor: Jerzy Leszek Copyright © 2011 Stavros J. Baloyannis. 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. Morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease, been associated with oxidative stress and Aβ-peptide-induced toxicity. We proceeded to estimation of mitochondria on electron micrographs of autopsy specimens of Alzheimer’s disease. We found substantial morphological and morphometric changes of the mitochondria in the neurons of the hippocampus, the neocortex, the cerebellar cortex, the thalamus, the globus pallidus, the red nucleus, the locus coeruleus, and the climbing fibers. The alterations consisted of considerable changes of the cristae, accumulation of osmiophilic material, and modification of the shape and size. Mitochondrial alterations were prominent in neurons, which showed a depletion of dendritic spines and loss of dendritic branches. Mitochondrial alterations are not related with the accumulation of amyloid deposits, but are prominent whenever fragmentation of the Golgi apparatus exists. Morphometric analysis showed also that mitochondria are significantly reduced in neurons, which demonstrated synaptic pathology. 1. Introduction which is one of the defining features, as real pathological hallmark, for the neuropathological diagnosis of the dis- Alzheimer’s disease (AD) is an insidiously progressive severe ease. In addition Alzheimer’s disease is characterized ultra- presenile and senile dementia, involving a number of cellular structurally by organelle pathology involving mostly the mi- and biochemical mechanisms, affecting millions of humans crotubules, the mitochondria, and Golgi apparatus [14]. as the most common cause of cognitive decline worldwide. From the etiological point of view it would be hypoth- From the clinical point of view AD is mostly character- esized that the multiple genetic loci [15, 16], associated ized by age-dependent cognitive decline affecting memory with familial Alzheimer’s disease would plead in favor of primarily, associated frequently with behavioral and mood the heterogeneity of the disease and support the idea that the phenomenological expression of Alzheimer’s disease is disorders, which increasingly appear as the disease advances [1]. the final consequence of various metabolic, neurochemical, and morphological alterations, based on a broad genetic From the neuropathological point of view, Alzheimer’s background [17], since accumulation of Aβ peptide at disease is mostly characterized by selective neuronal loss [2, 3], marked synaptic alterations [4–6], morphological mito- synaptic terminals may be associated with synaptic damage and cognitive decline in patients with AD [18]. chondrial abnormalities [7, 8], tau pathology [9] resulting Although the majority of familial or inherited AD, which in neurofibrillary degeneration (NFT) [10], inflammatory responses and mainly by extracellular extensive deposits of manifests at an early age, are often associated with mutations in AβPP [19], the vast majority of the sporadic ones, which polymers of Aβ peptide in the form of neuritic plaques [11, 12] in the neocortex, the hippocampus, and many sub- manifests usually at later stages of life, are proved to be multifactorial, including induced expression of AβPP [20– cortical structures, which are involved in cognitive function. 22] by pathological stimuli, environmental factors, as well as The production and accumulation of Aβ peptide are the result of the posttranslational proteolysis of the APP [13], deprivation of trophic factors. 2 International Journal of Alzheimer’s Disease Moreover the increased risk of Alzheimer’s disease in 2.3. Light Microscope, Golgi Staining, Golgi-Nissl Method. sporadic cases, when a maternal relative is afflicted with the The remaining parts of the above-mentioned areas of the disease pleads on the other hand in favor of a maternally brain and the cerebellum were processed for silver impreg- derived predisposition, was related probably to mitochon- nation techniques, according to rapid Golgi staining. Thus, after a four-week fixation in formalin they were immersed in drial DNA (mtDNA) [23]. Mitochondrial dysfunction on the potassium dichromate (7 g potassium dichromate in 300 mL other hand is associated with oxidative stress, which may water) for 10 days. Then they were immersed in 1% silver play an important role in the early pathogenetic stages of nitrate for 10 days. Following a rapid dehydration in graded Alzheimer’s disease [24, 25], presumably prior to the onset of the cognitive dysfunction since a substantial body of evidence alcohol solutions, the specimens were embedded in paraffin suggests that mitochondria play a crucial role in ageing- and cut, some of them at 100 μ and some at 25 μ,alterna- related neurodegenerative diseases [24]. tively. The sections of 25 μ were stained also with methylene blue, according to Golgi-Nissl method. All the sections were 2. Material and Methods mounted in permount, between two cover slips and studied in a Zeiss Axiolab Photomicroscope. 2.1. Patients. We studied the hippocampus, the acoustic cor- We estimated the dendritic arborization, the number of tex, the visual cortex, the thalamus, the globus pallidus, the locus coeruleus, the red nucleus, and many areas of the the branches, and the dendritic spines morphometrically in cerebellar cortex in ten brains of patients who suffered from light microscope in sections stained according to rapid Golgi Alzheimer’s disease, four men and six women, aged 62–87 method and Golgi-Nissl staining. years, who fulfilled the clinical, neuropsychological, and lab- oratory diagnostic criteria of Alzheimer’s disease. The mean 2.4. Statistical Analysis. Statistical analysis was based on the education of the patients was 15.2 years, and all of them t-test on the basis of 5000 mitochondria from 30 specimens spoke their native language fluently. Screening procedures of Alzheimer’s disease brains and 30 specimens of normal were applied included medical history, medical examination, control brains. cardiological investigation, and physical neurologic assess- ment, and psychiatric and neuropsychological examinations. All the patients underwent EEG, carotid duplex Doppler, 3. Results computerized tomography (CT) scanning and magnetic res- 3.1. Silver Impregnation Technique. Application of the silver onance imaging (MRI) of the brain, and single-photon emis- impregnation technique revealed neuronal loss and marked sion computed tomography (SPECT). abbreviation of the dendritic arborization in all the layers The mental status of the patients was assessed by Min- of the acoustic and the visual cortex, the hippocampus, the imental State Examination (MMSE) and dementia rating thalamus, the globus pallidus, the locus coeruleus, the red scale (DRS) [26] and ADAS-COX test. nucleus, and the cerebellar cortex. Layer I, of the acoustic The cause of death of the patients was heart arrest fol- and visual cortex, which includes Cajal-Retzius cells, which lowing to cardiac infarct one to seven months after the final normally develop very long horizontal axonic profiles [27, neurological assessment. 28], was practically empty of neurons in the patients who The postmortem examination of each one of the cases suffered from Alzheimer’s disease, in contrast to normal was performed within 6 h after death. control brains. Loss of tertiary dendritic branches was also noticed in the acoustic and the visual cortex in all of the specimens. 2.2. Electron Microscopy. Small samples from the hippocam- Abbreviation of the dendritic arborization was promi- pus (2 × 2 × 2 mm), the acoustic cortex, the visual cortex, nent mostly in the neurons of layers III and V of the acoustic the thalamus, the globus pallidus, the locus coeruleus, and and visual cortex, in the pyramidal neurons of the hip- from many areas of the cerebellar cortex were excised pocampus as well as in the polyhedral neurons of the locus and immersed in Sotelo’s fixing solution, composed of 1% coeruleus and the Purkinje cells of the cerebellar cortex, paraformaldehyde, 2.5% glutaraldehyde in cacodylate buffer which demonstrated also a marked decrease of the number 0.1 M, adjusted at pH 7.35. Then they were postfixed by of dendritic spines in comparison with the normal control immersion in 1% osmium tetroxide for 30 min at room tem- brains. perature and dehydrated in graded alcohol solutions and The axonic collaterals in layers III, IV, V, and VI of the propylene oxide. acoustic and visual cortex were dramatically decreased in Thin sections were cut in a Reichert ultratome, con- comparison with the normal controls. trasted with uranyl acetate and lead citrate, and studied in a Decrease of the branches of the apical dendrites of Zeiss 9aS electron microscope. the cortical neurons as well as decrease in spine density We also studied the morphology of the mitochondria, the was widespread phenomena seen in the large majority of Golgi apparatus, and the synapses and proceeded to morpho- the neurons of the acoustic and the visual cortex, in the metric estimations at electron microscope on micrographs of hippocampus, the thalamus, the globus pallidus, the red a standard magnification of 56.000x. nucleus, the locus coeruleus, and the cerebellar neurons. International Journal of Alzheimer’s Disease 3 Figure 2: Mossy fibers of the cerebellar cortex in a case of Alz- heimer’s disease showing decrease of the number of the synaptic vesicles and lack of mitochondria (mag. 65.000x). Figure 1: Dendritic profile of a Purkinje cell in a case of Alzheimer’s disease including elongated mitochondrion, showing disruption of the cristae. The presynaptic profile, presumably a terminal of par- allel fiber is characterized by the marked poverty of the synaptic vesicles (mag. 65.000x). 3.2. Electron Microscopy. Electron microscopy revealed path- ological alterations of the dendritic spines and impressive decrease in spine density in the secondary and tertiary den- dritic branches in all the layers of the acoustic and visual cortex. Reduction in spine size was prominent in neurons of layers II, III, and V. A substantial number of dendritic spines demonstrated large multivesicular bodies, dysmorphic spine apparatus, and mitochondria, which were characterized by marked morphological alterations. Figure 3: Small dense mitochondrion associated with fragmenta- Morphological alterations of the dendritic spines were tion of the cisternae of Golgi apparatus (meg. 70.000x). noticed also in the pyramidal neurons of the hippocampus, the large polyhedral neurons of the thalamus and the globus pallidus, the polyhedral neurons of the locus coeruleus as well as the Purkinje cells of the cerebellar hemispheres. Giant Many dendritic profiles contained mitochondria, which spines were seen mostly in the hippocampus and in the showed an impressive polymorphism in the arrangement of Purkinje cells of the cerebellum. the cristae, which sometimes showed a concentric configura- In large number of presynaptic terminals in the acoustic tion or in other places they were arranged in a parallel way and the visual cortex of the patients who suffered from to the long axis of the organelle. Some dendrites of Purkinje Alzheimer’s disease, the ultrastructural study revealed an cells and a substantial number of climbing fibres contained very large elongated mitochondria. impressive polymorphism and pleomorphism of the synaptic vesicles, which were dramatically decreased in number in Small round mitochondria intermixed with dense bodies comparison with normal control brains (Figure 1). or associated with fragmentation of the Golgi apparatus Impressive poverty of the synaptic vesicles was particu- (Figure 3) were seen in the soma of a considerable number larly seen in the presynaptic terminals in layers III, IV, and V of neurons of the visual cortex, the hippocampus, the locus of the acoustic and visual cortex as well as in the mossy fibers coeruleus, the red nucleus, the large polyhedral neurons of the cerebellar cortex (Figure 2). Decrease of the number of of globus pallidus, and the Purkinje cells of the cerebellar synaptic vesicles and marked polymorphism of the remained cortex in contrast to normal control brains, in which the vesicles was also seen in the hippocampus the thalamus, the mitochondria looked unremarkable. locus coeruleus, and in the parallel and climbing fibers of the It is worth to emphasize that morphological alterations of cerebellar cortex. the mitochondria were also seen in the soma, the perivascular Mitochondrial pathology was seen in the majority of the astrocytic processes, and the astrocytic sheaths in Alzheimer’s dendritic spines in all of the specimens, which consisted brains in contrast to normal controls. of substantial change of shape and size, fragmentation From the morphometric point of view the ellipsoid of cristae, and accumulation of osmiophilic material in a mitochondria in the dendritic spines of the normal control considerable number of mitochondria. brains appear to have an average diameter of 650 ± 250 nm 4 International Journal of Alzheimer’s Disease and a mean axial ratio of 1.9 ± 0.2. The round or global acts causally in disease pathogenesis. Mutations in mito- mitochondria in normal controls appeared as having a mean chondrial DNA and oxidative stress, on the other hand, may contribute to ageing, which is the substantial biological back- mitochondrial radius of 350 nm. ground for the majority of the neurodegenerative diseases In Alzheimer’s disease brains, the ellipsoid mitochondria [50]. Mitochondrial dysfunction has been associated with of the neurons of the acoustic and the visual cortex appear energy crisis of the cell and excitotoxic cell death and is to have an average diameter of 480 ± 250 nm and a mean considered to be of substantial importance in the cascade of axial ratio of 1.7 ± 0.2. The round mitochondria have a mean phenomena, which eventually lead to apoptosis. radius of 280 nm. Some observations in early cases of Alzheimer’s disease [51] indicate that morphological alterations of the mito- chondria and oxidative damage may be one of the earliest 4. Discussion events in Alzheimer’s disease. The morphological alteration of the mitochondria seen in subcortical centres, such as The mitochondria, which are the only nonnuclear con- in the thalamus, the globus pallidus, the red nucleus, and stituents of the cell with their own DNA (mtDNA), having the locus caeruleus, pleads in favor of a generalized mito- machinery for synthesizing RNA and proteins, are critical chondrial dysfunction in Alzheimer’s disease, which may be to homeostasis of the cell, by virtue of providing most of associated with wide neuronal loss and synaptic alterations, the energy for cellular processes and by their involvement seriously affecting consequently, the mental faculties, which in other metabolic pathways. Mitochondria are also critical are basically related to extensive neural networks [52]. regulators of cell apoptosis, as being involved in a con- Moreover, an impressive number of disease-specific proteins siderable number of neurodegenerative diseases [29, 30], interact with mitochondria. Well-documented studies [53] since it is well known that energy production, realized demonstrate that a significant amount of the N-terminal by oxidative phosphorylation, occurs in the mitochondria, domain of APP targeted the mitochondria of cortical neu- which generate most of the cell’s supply of ATP. ronal cells and select regions of the brain of a transgenic From the morphological point of view the shape and mouse model for AD. The accumulation of transmembrane- size of the mitochondria as well are highly variable [31], de- arrested APP blocked protein translocation, disrupted mito- pending on fission and fusion [32]. Their morphology is chondrial function, and impaired brain energy metabolism. sometimes controlled by cytoskeletal elements, namely the In Alzheimer’s disease the amyloid precursor protein has neurofilaments and the microtubules [33]. The change of the been localized to mitochondria as has the toxic amyloid shape of the mitochondria occurs mostly through their move beta peptide. The binding site for amyloid beta has been to axons, dendrites, and synaptic terminals via anterograde identified as alcohol dehydrogenase in the matrix space transport [34]. of the organelle. Many morphological alterations of AD During the various neuronal processes approximately could very well be linked to mitochondria changes since one-third of the mitochondria are in motion along micro- blockage of mitochondrial energy production shifts amyloid tubules and actin filaments [35–37], whereas the majority of protein precursor metabolism to the production of more them are stationary. Mitochondrial motility and accumula- amyloidogenic forms of amyloid [54]. In addition amyloid tion are coordinated, since mitochondria are transported to beta peptide promotes permeability transition pore in brain regions where ATP consumption and necessity for energy are mitochondria [55, 56]. particularly high, as it takes place in the synapses, which have It is important to mention that many protein systems high energy demand for serving neuronal communication are also essential in mitochondrial function, their mor- [38]. phological integrity and in binding to the cytoskeleton Mitochondrial alterations and dysfunction have been re- [57]. Mitochondrial porin is an outer-membrane protein ported in several neurodegenerative diseases [39–41] associ- that forms regulated channels (Voltage-Dependent Anionic ated mostly with oxidative damage [42] and vascular lesions Channels) between the mitochondrial intermembrane space [43]. Oxidative stress is mostly associated with amyloid β and the cytosol. Porin may play an important role in binding (Aβ) accumulation in the neocortex [7, 44, 45], playing to neurofilaments and microtubules [37], since porin-rich therefore an important role in the pathogenetic mechanisms domains contain most of the binding sites for MAP2 [58]. of Alzheimer’s disease [46], since it is not only involved In addition preselinin-2 modulates endoplasmic reticulum- in damage to the proteins of NFT [36] and the formation mitochondrial interactions [59], a fact that pleads in favour of senile plaques but also involves extensive damage to of the crucial role that mitochondria play in the pathogenetic the cytoplasm of neuronal populations vulnerable to death cascade of Alzheimer’s disease. during AD [47]. The number of the mitochondria varies, according to It is also well documented that Aβ peptide may increase energy state of the cell. Some evidence suggests that the mitochondrial reactive oxygen species (ROS) production mitochondria redistribute towards the dendritic profiles in [48], causing further impairment of mitochondrial function response to stimulation as a manifestation of synaptic plas- [49] since the lack of histones in mitochondrial DNA renders ticity [60]. Normally a limited number of dendritic spines them a vulnerable target to oxidative stress. contain mitochondria, which are mostly small and round, In all major examples of these diseases there is strong been increased in number inside the dendritic branches evidence that mitochondrial dysfunction occurs early and during the synaptogenesis. A decrease in energy metabolism International Journal of Alzheimer’s Disease 5 and altered cytochrome c oxidase (CytOX) activity are [14] S. 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Mitochondria Are Related to Synaptic Pathology in Alzheimer's Disease

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Copyright © 2011 Stavros J. Baloyannis. 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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SAGE-Hindawi Access to Research International Journal of Alzheimer’s Disease Volume 2011, Article ID 305395, 7 pages doi:10.4061/2011/305395 Clinical Study Mitochondria Are Related to Synaptic Pathology in Alzheimer’s Disease Stavros J. Baloyannis Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, 54006 Thessaloniki, Greece Correspondence should be addressed to Stavros J. Baloyannis, sibh844@otenet.gr Received 6 March 2011; Accepted 12 July 2011 Academic Editor: Jerzy Leszek Copyright © 2011 Stavros J. Baloyannis. 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. Morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease, been associated with oxidative stress and Aβ-peptide-induced toxicity. We proceeded to estimation of mitochondria on electron micrographs of autopsy specimens of Alzheimer’s disease. We found substantial morphological and morphometric changes of the mitochondria in the neurons of the hippocampus, the neocortex, the cerebellar cortex, the thalamus, the globus pallidus, the red nucleus, the locus coeruleus, and the climbing fibers. The alterations consisted of considerable changes of the cristae, accumulation of osmiophilic material, and modification of the shape and size. Mitochondrial alterations were prominent in neurons, which showed a depletion of dendritic spines and loss of dendritic branches. Mitochondrial alterations are not related with the accumulation of amyloid deposits, but are prominent whenever fragmentation of the Golgi apparatus exists. Morphometric analysis showed also that mitochondria are significantly reduced in neurons, which demonstrated synaptic pathology. 1. Introduction which is one of the defining features, as real pathological hallmark, for the neuropathological diagnosis of the dis- Alzheimer’s disease (AD) is an insidiously progressive severe ease. In addition Alzheimer’s disease is characterized ultra- presenile and senile dementia, involving a number of cellular structurally by organelle pathology involving mostly the mi- and biochemical mechanisms, affecting millions of humans crotubules, the mitochondria, and Golgi apparatus [14]. as the most common cause of cognitive decline worldwide. From the etiological point of view it would be hypoth- From the clinical point of view AD is mostly character- esized that the multiple genetic loci [15, 16], associated ized by age-dependent cognitive decline affecting memory with familial Alzheimer’s disease would plead in favor of primarily, associated frequently with behavioral and mood the heterogeneity of the disease and support the idea that the phenomenological expression of Alzheimer’s disease is disorders, which increasingly appear as the disease advances [1]. the final consequence of various metabolic, neurochemical, and morphological alterations, based on a broad genetic From the neuropathological point of view, Alzheimer’s background [17], since accumulation of Aβ peptide at disease is mostly characterized by selective neuronal loss [2, 3], marked synaptic alterations [4–6], morphological mito- synaptic terminals may be associated with synaptic damage and cognitive decline in patients with AD [18]. chondrial abnormalities [7, 8], tau pathology [9] resulting Although the majority of familial or inherited AD, which in neurofibrillary degeneration (NFT) [10], inflammatory responses and mainly by extracellular extensive deposits of manifests at an early age, are often associated with mutations in AβPP [19], the vast majority of the sporadic ones, which polymers of Aβ peptide in the form of neuritic plaques [11, 12] in the neocortex, the hippocampus, and many sub- manifests usually at later stages of life, are proved to be multifactorial, including induced expression of AβPP [20– cortical structures, which are involved in cognitive function. 22] by pathological stimuli, environmental factors, as well as The production and accumulation of Aβ peptide are the result of the posttranslational proteolysis of the APP [13], deprivation of trophic factors. 2 International Journal of Alzheimer’s Disease Moreover the increased risk of Alzheimer’s disease in 2.3. Light Microscope, Golgi Staining, Golgi-Nissl Method. sporadic cases, when a maternal relative is afflicted with the The remaining parts of the above-mentioned areas of the disease pleads on the other hand in favor of a maternally brain and the cerebellum were processed for silver impreg- derived predisposition, was related probably to mitochon- nation techniques, according to rapid Golgi staining. Thus, after a four-week fixation in formalin they were immersed in drial DNA (mtDNA) [23]. Mitochondrial dysfunction on the potassium dichromate (7 g potassium dichromate in 300 mL other hand is associated with oxidative stress, which may water) for 10 days. Then they were immersed in 1% silver play an important role in the early pathogenetic stages of nitrate for 10 days. Following a rapid dehydration in graded Alzheimer’s disease [24, 25], presumably prior to the onset of the cognitive dysfunction since a substantial body of evidence alcohol solutions, the specimens were embedded in paraffin suggests that mitochondria play a crucial role in ageing- and cut, some of them at 100 μ and some at 25 μ,alterna- related neurodegenerative diseases [24]. tively. The sections of 25 μ were stained also with methylene blue, according to Golgi-Nissl method. All the sections were 2. Material and Methods mounted in permount, between two cover slips and studied in a Zeiss Axiolab Photomicroscope. 2.1. Patients. We studied the hippocampus, the acoustic cor- We estimated the dendritic arborization, the number of tex, the visual cortex, the thalamus, the globus pallidus, the locus coeruleus, the red nucleus, and many areas of the the branches, and the dendritic spines morphometrically in cerebellar cortex in ten brains of patients who suffered from light microscope in sections stained according to rapid Golgi Alzheimer’s disease, four men and six women, aged 62–87 method and Golgi-Nissl staining. years, who fulfilled the clinical, neuropsychological, and lab- oratory diagnostic criteria of Alzheimer’s disease. The mean 2.4. Statistical Analysis. Statistical analysis was based on the education of the patients was 15.2 years, and all of them t-test on the basis of 5000 mitochondria from 30 specimens spoke their native language fluently. Screening procedures of Alzheimer’s disease brains and 30 specimens of normal were applied included medical history, medical examination, control brains. cardiological investigation, and physical neurologic assess- ment, and psychiatric and neuropsychological examinations. All the patients underwent EEG, carotid duplex Doppler, 3. Results computerized tomography (CT) scanning and magnetic res- 3.1. Silver Impregnation Technique. Application of the silver onance imaging (MRI) of the brain, and single-photon emis- impregnation technique revealed neuronal loss and marked sion computed tomography (SPECT). abbreviation of the dendritic arborization in all the layers The mental status of the patients was assessed by Min- of the acoustic and the visual cortex, the hippocampus, the imental State Examination (MMSE) and dementia rating thalamus, the globus pallidus, the locus coeruleus, the red scale (DRS) [26] and ADAS-COX test. nucleus, and the cerebellar cortex. Layer I, of the acoustic The cause of death of the patients was heart arrest fol- and visual cortex, which includes Cajal-Retzius cells, which lowing to cardiac infarct one to seven months after the final normally develop very long horizontal axonic profiles [27, neurological assessment. 28], was practically empty of neurons in the patients who The postmortem examination of each one of the cases suffered from Alzheimer’s disease, in contrast to normal was performed within 6 h after death. control brains. Loss of tertiary dendritic branches was also noticed in the acoustic and the visual cortex in all of the specimens. 2.2. Electron Microscopy. Small samples from the hippocam- Abbreviation of the dendritic arborization was promi- pus (2 × 2 × 2 mm), the acoustic cortex, the visual cortex, nent mostly in the neurons of layers III and V of the acoustic the thalamus, the globus pallidus, the locus coeruleus, and and visual cortex, in the pyramidal neurons of the hip- from many areas of the cerebellar cortex were excised pocampus as well as in the polyhedral neurons of the locus and immersed in Sotelo’s fixing solution, composed of 1% coeruleus and the Purkinje cells of the cerebellar cortex, paraformaldehyde, 2.5% glutaraldehyde in cacodylate buffer which demonstrated also a marked decrease of the number 0.1 M, adjusted at pH 7.35. Then they were postfixed by of dendritic spines in comparison with the normal control immersion in 1% osmium tetroxide for 30 min at room tem- brains. perature and dehydrated in graded alcohol solutions and The axonic collaterals in layers III, IV, V, and VI of the propylene oxide. acoustic and visual cortex were dramatically decreased in Thin sections were cut in a Reichert ultratome, con- comparison with the normal controls. trasted with uranyl acetate and lead citrate, and studied in a Decrease of the branches of the apical dendrites of Zeiss 9aS electron microscope. the cortical neurons as well as decrease in spine density We also studied the morphology of the mitochondria, the was widespread phenomena seen in the large majority of Golgi apparatus, and the synapses and proceeded to morpho- the neurons of the acoustic and the visual cortex, in the metric estimations at electron microscope on micrographs of hippocampus, the thalamus, the globus pallidus, the red a standard magnification of 56.000x. nucleus, the locus coeruleus, and the cerebellar neurons. International Journal of Alzheimer’s Disease 3 Figure 2: Mossy fibers of the cerebellar cortex in a case of Alz- heimer’s disease showing decrease of the number of the synaptic vesicles and lack of mitochondria (mag. 65.000x). Figure 1: Dendritic profile of a Purkinje cell in a case of Alzheimer’s disease including elongated mitochondrion, showing disruption of the cristae. The presynaptic profile, presumably a terminal of par- allel fiber is characterized by the marked poverty of the synaptic vesicles (mag. 65.000x). 3.2. Electron Microscopy. Electron microscopy revealed path- ological alterations of the dendritic spines and impressive decrease in spine density in the secondary and tertiary den- dritic branches in all the layers of the acoustic and visual cortex. Reduction in spine size was prominent in neurons of layers II, III, and V. A substantial number of dendritic spines demonstrated large multivesicular bodies, dysmorphic spine apparatus, and mitochondria, which were characterized by marked morphological alterations. Figure 3: Small dense mitochondrion associated with fragmenta- Morphological alterations of the dendritic spines were tion of the cisternae of Golgi apparatus (meg. 70.000x). noticed also in the pyramidal neurons of the hippocampus, the large polyhedral neurons of the thalamus and the globus pallidus, the polyhedral neurons of the locus coeruleus as well as the Purkinje cells of the cerebellar hemispheres. Giant Many dendritic profiles contained mitochondria, which spines were seen mostly in the hippocampus and in the showed an impressive polymorphism in the arrangement of Purkinje cells of the cerebellum. the cristae, which sometimes showed a concentric configura- In large number of presynaptic terminals in the acoustic tion or in other places they were arranged in a parallel way and the visual cortex of the patients who suffered from to the long axis of the organelle. Some dendrites of Purkinje Alzheimer’s disease, the ultrastructural study revealed an cells and a substantial number of climbing fibres contained very large elongated mitochondria. impressive polymorphism and pleomorphism of the synaptic vesicles, which were dramatically decreased in number in Small round mitochondria intermixed with dense bodies comparison with normal control brains (Figure 1). or associated with fragmentation of the Golgi apparatus Impressive poverty of the synaptic vesicles was particu- (Figure 3) were seen in the soma of a considerable number larly seen in the presynaptic terminals in layers III, IV, and V of neurons of the visual cortex, the hippocampus, the locus of the acoustic and visual cortex as well as in the mossy fibers coeruleus, the red nucleus, the large polyhedral neurons of the cerebellar cortex (Figure 2). Decrease of the number of of globus pallidus, and the Purkinje cells of the cerebellar synaptic vesicles and marked polymorphism of the remained cortex in contrast to normal control brains, in which the vesicles was also seen in the hippocampus the thalamus, the mitochondria looked unremarkable. locus coeruleus, and in the parallel and climbing fibers of the It is worth to emphasize that morphological alterations of cerebellar cortex. the mitochondria were also seen in the soma, the perivascular Mitochondrial pathology was seen in the majority of the astrocytic processes, and the astrocytic sheaths in Alzheimer’s dendritic spines in all of the specimens, which consisted brains in contrast to normal controls. of substantial change of shape and size, fragmentation From the morphometric point of view the ellipsoid of cristae, and accumulation of osmiophilic material in a mitochondria in the dendritic spines of the normal control considerable number of mitochondria. brains appear to have an average diameter of 650 ± 250 nm 4 International Journal of Alzheimer’s Disease and a mean axial ratio of 1.9 ± 0.2. The round or global acts causally in disease pathogenesis. Mutations in mito- mitochondria in normal controls appeared as having a mean chondrial DNA and oxidative stress, on the other hand, may contribute to ageing, which is the substantial biological back- mitochondrial radius of 350 nm. ground for the majority of the neurodegenerative diseases In Alzheimer’s disease brains, the ellipsoid mitochondria [50]. Mitochondrial dysfunction has been associated with of the neurons of the acoustic and the visual cortex appear energy crisis of the cell and excitotoxic cell death and is to have an average diameter of 480 ± 250 nm and a mean considered to be of substantial importance in the cascade of axial ratio of 1.7 ± 0.2. The round mitochondria have a mean phenomena, which eventually lead to apoptosis. radius of 280 nm. Some observations in early cases of Alzheimer’s disease [51] indicate that morphological alterations of the mito- chondria and oxidative damage may be one of the earliest 4. Discussion events in Alzheimer’s disease. The morphological alteration of the mitochondria seen in subcortical centres, such as The mitochondria, which are the only nonnuclear con- in the thalamus, the globus pallidus, the red nucleus, and stituents of the cell with their own DNA (mtDNA), having the locus caeruleus, pleads in favor of a generalized mito- machinery for synthesizing RNA and proteins, are critical chondrial dysfunction in Alzheimer’s disease, which may be to homeostasis of the cell, by virtue of providing most of associated with wide neuronal loss and synaptic alterations, the energy for cellular processes and by their involvement seriously affecting consequently, the mental faculties, which in other metabolic pathways. Mitochondria are also critical are basically related to extensive neural networks [52]. regulators of cell apoptosis, as being involved in a con- Moreover, an impressive number of disease-specific proteins siderable number of neurodegenerative diseases [29, 30], interact with mitochondria. Well-documented studies [53] since it is well known that energy production, realized demonstrate that a significant amount of the N-terminal by oxidative phosphorylation, occurs in the mitochondria, domain of APP targeted the mitochondria of cortical neu- which generate most of the cell’s supply of ATP. ronal cells and select regions of the brain of a transgenic From the morphological point of view the shape and mouse model for AD. The accumulation of transmembrane- size of the mitochondria as well are highly variable [31], de- arrested APP blocked protein translocation, disrupted mito- pending on fission and fusion [32]. Their morphology is chondrial function, and impaired brain energy metabolism. sometimes controlled by cytoskeletal elements, namely the In Alzheimer’s disease the amyloid precursor protein has neurofilaments and the microtubules [33]. The change of the been localized to mitochondria as has the toxic amyloid shape of the mitochondria occurs mostly through their move beta peptide. The binding site for amyloid beta has been to axons, dendrites, and synaptic terminals via anterograde identified as alcohol dehydrogenase in the matrix space transport [34]. of the organelle. Many morphological alterations of AD During the various neuronal processes approximately could very well be linked to mitochondria changes since one-third of the mitochondria are in motion along micro- blockage of mitochondrial energy production shifts amyloid tubules and actin filaments [35–37], whereas the majority of protein precursor metabolism to the production of more them are stationary. Mitochondrial motility and accumula- amyloidogenic forms of amyloid [54]. In addition amyloid tion are coordinated, since mitochondria are transported to beta peptide promotes permeability transition pore in brain regions where ATP consumption and necessity for energy are mitochondria [55, 56]. particularly high, as it takes place in the synapses, which have It is important to mention that many protein systems high energy demand for serving neuronal communication are also essential in mitochondrial function, their mor- [38]. phological integrity and in binding to the cytoskeleton Mitochondrial alterations and dysfunction have been re- [57]. Mitochondrial porin is an outer-membrane protein ported in several neurodegenerative diseases [39–41] associ- that forms regulated channels (Voltage-Dependent Anionic ated mostly with oxidative damage [42] and vascular lesions Channels) between the mitochondrial intermembrane space [43]. Oxidative stress is mostly associated with amyloid β and the cytosol. Porin may play an important role in binding (Aβ) accumulation in the neocortex [7, 44, 45], playing to neurofilaments and microtubules [37], since porin-rich therefore an important role in the pathogenetic mechanisms domains contain most of the binding sites for MAP2 [58]. of Alzheimer’s disease [46], since it is not only involved In addition preselinin-2 modulates endoplasmic reticulum- in damage to the proteins of NFT [36] and the formation mitochondrial interactions [59], a fact that pleads in favour of senile plaques but also involves extensive damage to of the crucial role that mitochondria play in the pathogenetic the cytoplasm of neuronal populations vulnerable to death cascade of Alzheimer’s disease. during AD [47]. The number of the mitochondria varies, according to It is also well documented that Aβ peptide may increase energy state of the cell. 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