Open access peer-reviewed chapter

Mitochondria and Alzheimer’s Disease: An Electron Microscopy Study

Written By

Stavros J. Baloyannis

Submitted: October 10th, 2018Reviewed: January 31st, 2019Published: September 25th, 2019

DOI: 10.5772/intechopen.84881

Chapter metrics overview

1,052 Chapter Downloads

View Full Metrics

Abstract

Alzheimer’s disease is a progressive, irreversible presenile or senile neurodegenerative disorder, implicating mainly the mental faculties, characterized by decline of memory and judgment, learning impairment, loss of professional skills and verbal capacities, alterations of social behavior, decline of motor skills and eventual disarrangement of the autonomic equilibrium. Among the pathogenetic factors, oxidative stress and mitochondrial dysfunction may play an essential role. Alterations of mitochondria may enhance amyloid toxicity, which in turn may aggravate mitochondrial dysfunction. We describe ultrastructural alterations of mitochondria in the soma of neurons, in axons, dendritic profiles and synaptic terminals, in astrocytes in early cases of Alzheimer’s disease on various areas of the cerebral and the cerebellar cortex, the hippocampus, the hypothalamus, the mammillary bodies and the medial geniculate body. The morphological and morphometric study of the mitochondria revealed an impressive polymorphism at any area of the brain. The mitochondria demonstrated variation of size and shape, fragmentation of the cristae and marked changes of their structure. The most dramatic mitochondrial alterations were observed in dendritic profiles, spines and synaptic terminals. A substantial number of astrocytes demonstrated mitochondrial alterations, which coexisted with fragmentation of Golgi apparatus and dilatation of the cisternae of the smooth endoplasmic reticulum. On the basis of our observations, we feel that therapeutic strategies aiming at protecting the mitochondria might be beneficial in the treatment of early cases of AD.

Keywords

  • Alzheimer’s disease
  • mitochondria
  • Golgi apparatus
  • astrocytes
  • synapses
  • electron microscopy

1. Introduction

Alzheimer’s disease (AD) is one of the most enigmatic and multidimensional neurodegenerative diseases of the brain. The high incidence in aging, the ongoing number of the patients and the social, humanitarian and economic impact of the disease [1], as well as the irreversible course of the disease, the failure of therapeutic interventions [2] and the fatal outcome impose on the neuroscientists and the society a combined attempt for the amelioration of the quality of life of the patients at least by the reduction of risk factors in the initial stages of the disease [3].

The clinical manifestation of Alzheimer’s disease, starting from the inability to encode new memories, includes progressive and irreversible cognitive decline, affecting memory and judgment, loss of professional skills and verbal capacities, impairment of learning new informations and gradual disarrangement of the social behavior [4, 5] resulting in isolation of the patient in the framework of an obvious functional incapacity, encountering in vegetative state eventually.

The neuropathological background of AD mostly consists of selective neuronal loss [6, 7], substantial morphological and morphometric alterations of the synapses [8, 9, 10, 11], marked mitochondrial alterations, even in the initial stages of the disease [12, 13], tau pathology [14] resulting in the formation of neurofibrillary tangles (NFT) by the accumulation of hyperphosphorylated tau protein [15], many inflammatory phenomena, alterations of brain capillaries [16] and various extensive extracellular deposits of Aβ peptide’s polymers, in the form of polymorphic neuritic plaques, [17, 18].

Pathological alterations of the organelles in the soma, the axons, the dendrites and the synapses of neurons are observed in electron microscopy, even in the initial stage of the disease [19] in areas with minimal typical Alzheimer’s pathology, namely aggregations of Aβ peptide and neurofibrillary tangles. The majority of the alterations of the organelles in Alzheimer’s disease particularly concern the Golgi complex [19], the microtubules, the synaptic vesicles and mostly the mitochondria [20, 21, 22].

The etiopathology of the sporadic cases of Alzheimer’s disease remains a real problem in spite of the multidimensional extensive ongoing research in the last decades [23, 24] on the crucial fields of genetics [25, 26], molecular biology [27, 28], neuropathology [29, 30], neuroimmunology [31, 32], pathophysiology [33], neuroimaging [34] and neurochemistry [35, 36, 37, 38].

The pathogenetic mechanisms embrace a diverse range of hypotheses which attempt to decipher the real cause of memory and reasoning decline in AD. Among the many hypothesis, the most mattering are (a) the amyloid hypothesis [39, 40], (b) the metabolic and synaptic dysfunction hypothesis [41], (c) the hypothesis of translational neurodegeneration [42], (d) the tau hypothesis [43], (e) the hypothesis of neuroinflammation [44], (f) the cholinergic hypothesis [45], (g) the oxidative stress [46], (h) the vascular hypothesis [47, 48], (i) the glucose hypometabolism hypothesis [49], (j) the autoimmune hypothesis [50], (k) the endocrine hypothesis [51, 52], (l) the mitochondrial dysfunction [53, 54] and (m) the Golgi complex hypothesis [55, 56, 57].

Many of those hypotheses are basely interrelated, such as the amyloid hypothesis and the oxidative stress ones [58, 59], the amyloid and the tau hypothesis [60], the oxidative stress and the mitochondrial dysfunction [61], the mitochondrial dysfunction, energy deficiency and oxidative stress [6162], the mitochondria dysfunction and the synaptic pathology [22, 63], the tau pathology and the vascular hypothesis [64], the cholinergic dysfunction and the amyloid hypothesis [65], amyloid, tau and neurodegeneration hypothesis [66], the mitochondria and the dendritic hypothesis [67, 68, 69] and the immune reactions, microglia, tau, Aβ peptide, lipid processing and neurodegeneration hypothesis [70, 71, 72, 73].

Mitochondria hypothesis advocates in favor of the important role that mitochondrial dysfunction may play in the early stages of Alzheimer’s disease [21] by inducing energy deficiency and oxidative stress [22], which would be associated with β-amyloid (Aβ) neurotoxicity. It is well known that mitochondria, which has been defined as organelles in tissue culture since 1914 [74] are normally involved in aging process [75, 76, 77], since mitochondrial function declines as the age advances, resulting in decrease of ATP production and increase of free oxygen radicals formation, given that ATP synthase is located in the inner mitochondrial membrane, playing a key role in the energy homeostasis of the cell.

In addition, morphological alterations of mitochondria, resulting in deficiency of mitochondrial electron transport proteins, with considerable consequences upon the energy supply of nerve cells have been described in Alzheimer’s disease and other degenerative conditions of the brain [12, 21, 78, 79], which are also associated with oxidative stress [80].

It is also particularly noticeable that morphological abnormalities of mitochondria are seen in neurons lacking neurofibrillary tangles [12] suggesting that mitochondrial degeneration might be among the earliest signs of Alzheimer’s morphological alterations.

The fact that maternal influence seems to be a risk factor for Alzheimer’s disease morbidity, according to epidemiologic studies [81, 82], and to combined neuropsychological and neuroimaging investigations [83] plead in favor of the substantial role that mitochondria may also play in the pathogenetic cascade of Alzheimer’s disease.

In this perspective article, we attempted to describe the ultrastructural alterations of mitochondria in various neocortical and subcortical areas of the brain of patients who suffered from Alzheimer’s disease at the early stages.

Advertisement

2. Material and methods

2.1 Material

This electron microscope study is based on examination of 25 brains obtained at autopsy 2–7 hours after death at a room temperature of 40°C. All of the brains were derived from patients aged 55–80 years, who have had a history of dementia, which was definitely diagnosed 1 or 3 years prior to the end of their life.

The patients fulfilled on repeated clinical examinations and assessments all the psychological, psychiatric and neurological criteria of AD [84, 85, 86]. The patients have had 18 years of education, and had a fluency in their native language, two of them being also bilingual with equal fluency in both of the languages. The usual diagnostic assessment was based on the medical history, the physical examination, including cardiological investigation, neurological examination, psychiatric evaluation and detailed neuropsychological testing.

The cognition of the patients was evaluated by battery of neuropsychological testing [87], including mini mental state examination (MMSE) [88, 89], dementia rating scale (DRS) [90, 91], ADAS-COX test [92, 93] and the brief memory executive test (BMET) [94].

All the patients underwent an EEG examination and a carotid examination by duplex Doppler. Neuroimaging was performed including computerized tomography (CT), magnetic resonance imaging (MRI) of the brain and a single-photon emission computed tomography (SPECT) [95]. All the methods of clinical and laboratory investigations were evocative for Alzheimer’s disease. The patients passed away due to heart arrest.

In addition, we dissected and examined in electron microscopy 25 brains, which were unremarkable from the neuropathological point of view, derived from apparently healthy individuals of the same age range with the AD patients, using them as normal controls.

2.2 Methods

2.2.1 Electron microscopy

Multiple samples of a small size (2 × 2 × 2 mm) were excised from the hippocampus, the prefrontal area of the cortex, the superior parietal lobe, the occipital pole, the visual cortex, the Hessl gyri of the temporal neocortex, the vermis of the cerebellum and the cerebellar hemispheres, the hypothalamus, the mammillary bodies and the medial geniculate bodies. The samples were selected bilaterally and immersed directly in Sotelo’s fixing solution [96], composed of 1% paraformaldehyde, 2.5% glutaraldehyde in cacodylate buffer 0.1 M, adjusted at pH 7.35.

Then all the specimens were post fixed in 1% osmium tetroxide for 30 min at a room temperature of 18°C and dehydrated in graded alcohol solutions and in propylene oxide twice. After dehydration, the specimens were embedded in araldite mixture and cut in ultrathin sections by a Reichert ultratome.

The sections were placed on the grids where they were contrasted with uranyl acetate and lead citrate, and studied in a Zeiss electron microscope of the type 9aS.

The study electron microscopy examination was particularly focused on the morphology of the organelles, mainly on the mitochondria of neurons and astrocytes. In addition, the Golgi complex, the endoplasmic reticulum, the endosomes, the dendritic profiles, the spines, the axons, the axonic collaterals and the synaptic components were studies in all of the sections.

The morphometric estimation was carried out on micrographs of a standard magnification of 56,000×. The analysis of each macrograph was performed with an image analyzer. The surface area of mitochondria as well as the volume and the circularity ratio (CR) were calculated on a total of 8000 mitochondria.

The statistical analysis of the data was evaluated by Student t tests.

Advertisement

3. Results

The ultrastructural study of the mitochondria revealed an impressive polymorphism at any area of the brain. The mitochondria demonstrated a wide variation of size and shape in the soma, the axons, the dendrites and the synaptic terminals in the majority of the neurons (Figure 1). The majority of the mitochondria demonstrated fragmentation of the cristae and obvious disarrangement of their interior structure (Figures 1 and 2). The mitochondria in the presynaptic terminals were either small and round with few cristae (Figure 3) or very large showing disruption of the cristae (Figure 4).

Figure 1.

Large round mitochondrion in a dendritic profile in the molecular layer of the cerebellum in a case of AD. Electron micrograph Mag. 248,000×.

Figure 2.

Large mitochondrion in a postsynaptic terminal in the molecular layer of the cerebellum in a case of AD. The disruption of the mitochondrial cristae is obvious. Electron micrograph Mag. 248,000×.

Figure 3.

Small round mitochondria in Purkinje cell dendritic spines (postsynaptic components) in the molecular layer of the cerebellum in a case of AD. Electron micrograph Mag. 248,000×.

Figure 4.

Very large mitochondria in dendritic profiles (d) and dendritic spines (ds) in the molecular layer of the cerebellum in a case of AD. The disruption of the mitochondrial cristae and the disarrangement of the interior structure are obvious. Electron micrograph Mag. 56,000×.

It should be underlined that in areas of the brain with minimal Alzheimer’s pathology, such as the cerebellum, the visual, the acoustic cortex, the mammillary bodies and the hypothalamus, mitochondria demonstrated obvious morphological alterations. Very large mitochondria were observed in the soma and the dendritic profiles of Purkinje cells (Figure 5), in the granule cells (Figure 6) as well as in the climbing fibers, the mossy fibers and the synaptic terminals of parallel fibers (Figure 7). Large number of small mitochondria with disruption of cristae was observed in the visual cortex (Figure 8) and the acoustic cortex (Figure 9).

Figure 5.

Very elongated and large mitochondria in dendritic profiles (d) and dendritic spines (ds) in the molecular layer of the vermis of the cerebellum in a case of AD. The presynaptic terminals of the parallel fibers (pf) contain small round dense mitochondria. Electron micrograph Mag. 124,000×.

Figure 6.

Large abnormal mitochondria (m) in the perikaryon of a granule cell (GC) of the vermis of the cerebellum in a case of AD. Electron micrograph Mag. 124,000×.

Figure 7.

Small dense mitochondria in a presynaptic terminal (pst) of a parallel fiber (pf) in contact with a large dendritic branch of Purkinje cell (PCd) in the molecular layer of the left cerebellar hemisphere in a case of AD. Electron micrograph Mag. 124,000×.

Figure 8.

Mitochondria with obvious disruption of the cristae in presynaptic terminal (prs) in the visual cortex in a case of AD. Electron micrograph Mag. 124,000×.

Figure 9.

Small dense mitochondria in postsynaptic terminal (ps) in the acoustic cortex in a case of AD. Electron micrograph Mag. 124,000×.

Mitochondrial alterations were also observed in many synaptic profiles in the suprachiasmatic and the paraventricular hypothalamic nuclei of AD brains (Figure 10).

Figure 10.

Small abnormal mitochondria with disruption of the cristae and disintegration of the interior structure in the suprachiasmatic nucleus of the hypothalamus in a case of AD. Electron micrograph Mag. 124,000×.

The morphometric estimation of the mitochondria in the soma, the dendrites and the dendritic spines of a considerable number of neurons of the suprachiasmatic nucleus in AD brains revealed that they have an average diameter of 440 ± 250 nm and a mean axial ratio of 1.7 ± 0.2 [97].

The polymorphism of the mitochondria was the most frequent finding at any studied area of the cortex of the brain hemispheres, the cerebellum and the subcortical structures. Small round mitochondria intermixed with very large ones with disarrangement of the cristae and accumulation of fibrillary elements (Figure 11) or dense osmiophilic material (Figure 12). The mitochondria in the dendritic profiles and the synaptic terminals at the prefrontal cortex were large occupying the majority of the volume of the synaptic component (Figure 1). Large mitochondria were also observed in axonic collaterals among the myelinated fibers at the prefrontal and the parietal cortices (Figure 13). Small mitochondria were frequently observed in association with Golgi complex alterations in the soma of neurons and astrocytes (Figure 14).

Figure 11.

Very large mitochondria (m) intermixed with small ones (m) in a dendritic profile of Purkinje cell (PCd) in the vermis of the cerebellum in a case of AD. Electron micrograph Mag. 124,000×.

Figure 12.

Very small dense mitochondria in an axonic profile (ax) in the acoustic cortex in a case of AD. Electron micrograph Mag. 124,000×.

Figure 13.

Large mitochondrion in an axonic collateral among myelinated fibers in the prefrontal area of the cortex in a case of AD. Electron micrograph Mag. 124,000×.

Figure 14.

Small mitochondrion (m) near dilated cisternae of Golgi apparatus (GA) and multivesicular body (mvb) in the soma of an astrocyte in the prefrontal area of the cortex of a case of AD. Electron micrograph Mag. 54,000×.

A substantial number of astrocytes demonstrated small or very large mitochondria with disruption of the cristae in association with dilated cisternae of the smooth endoplasmic reticulum (Figure 15). Small mitochondria were also observed in oligodendrocytes in the subcortical white mater in association with dilated cisternae of the smooth endoplasmic reticulum and alterations of the Golgi complex (Figure 16).

Figure 15.

Small mitochondria (m) among dilated cisternae of smooth endoplasmic reticulum (er) in the soma of an astrocyte in the parietal cortex of a case of AD. Electron micrograph Mag. 54,000×.

Figure 16.

Small mitochondria (m) among dilated cisternae of smooth endoplasmic reticulum (er) and fragmented cisternae of Golgi apparatus in the soma of an oligodendrocyte in the subcortical white matter of the parietal lobe of a case of AD. Electron micrograph Mag. 54,000×.

The dendritic spines of the cortical neurons were dramatically reduced in number and size and most of the presynaptic terminals included small round and dense mitochondria and were also characterized by the dramatic poverty of the synaptic vesicles (Figure 17), a finding advocating in favor of a previous concept that the morphological alterations of the synapses and dendritic spines coincide, as a rule, with marked mitochondrial alterations [22].

Figure 17.

Small mitochondria (m) in presynaptic profiles which show a dramatic poverty of synaptic vesicles (v) in the molecular layer of the cerebellum of AD. Electron micrograph Mag. 124,000×.

In morphometric estimation, the mitochondria in normal control aged brains appeared to have an average diameter of 250–650 nm and a mean axial ratio of 1.9 ± 0.2. The round or global mitochondria in normal controls appeared to have a mean mitochondrial radius of 350 nm. In Alzheimer’s disease, ellipsoid mitochondria of Purkinje cells appeared to have an average diameter of 250–510 nm and a mean axial ratio of 1.7 ± 0.2. Round mitochondria were characterized by a mean radius of 280 nm.

Advertisement

4. Discussion

Mitochondria play an essential role in energy supply of the cells, given that they provide most of the energy by oxidative phosphorylation of glucose, been basely key organelles for energy production involved in many metabolic pathways of the cell [98]. Mitochondrial dysfunction, associated with aging may be also a crucial factor in neurodegenerative disorders including Alzheimer’s disease.

Decrease in energy metabolism and altered cytochrome C oxidase (CytOX) activity are among the earliest detectable defects in AD [99], affecting presumably neuronal plasticity and synaptogenesis. It is important to underline that reduced respiratory activity has also been reported in platelets of patients who suffered from AD [100], in the early stages of the disease. In addition, postmortem cytochrome-C oxidase activity is lower than normal in the cerebral cortex and in the platelets of AD patients [101] and mutations in cytochrome-C oxidase genes have been reported in late-onset AD [102].

Mitochondria and mtDNA are very sensitive to oxidative damage, such as protein oxidation and lipid peroxidation and inversely mitochondrial alterations may induce or enhance the existing oxidative stress, a fact pleading for an intimate and early association between oxidative stress and mitochondrial abnormalities [103, 104].

In addition, the combined effect of high calcium ions with oxidative stress may induce serious impairment of the mitochondrial function, leading to release of cytochrome C and triggering the initiation of the intrinsic pathway for apoptosis in many systems [105, 106, 107].

Oxidative stress can also enhance the production and the aggregation of Aβ [108] as well as the hyperphosphorylation of tau protein, which contribute extensively in the pathogenetic mechanism of AD [109]. The overproduction of Aβ peptide in AD induces fission and fragmentation of mitochondria, a fact that further increases oxidative stress and causes a considerable decline of energy production, which is associated with the increased expression of dynamin-related protein 1 (Drp1) [110]. The Aβ peptide enhances the activity of Drp1 protein in neurons, which subsequently induces morphological alteration of the mitochondria and increases the mitochondrial dysfunction in AD.

Mitochondrial alterations are closely connected with the over expression of the amyloid precursor protein (APP) and the amyloid-β peptide [58]. The Aβ peptides are generated either extracellularly or within the cisternae of the endoplasmic reticulum (ER) and the mitochondria. APP is folded and modified in the ER and transported through the Golgi complex to the plasma membrane. Transmembrane arrest of APP causes considerable impairment of mitochondrial function in neurons [111].

A substantial amount of amyloid-β peptide is generated in mitochondria-associated ER membranes (ER-MAMs or MAMs), which is a dynamic sub-compartment of the ER, which is connected with mitochondria [112]. In Alzheimer’s disease, intraneuronal amyloid precursor protein and amyloid-β are mostly localized to mitochondria [112], where amyloid-β peptide may induce mitochondrial dysfunctions by interaction with cyclophilin D, which is a subunit of the mitochondrial permeability transition pore [113]. Amyloid-β peptide may also interact with Aβ binding alcohol dehydrogenase (ABAD) on the mitochondrial membranes and induce further mitochondrial dysfunction [114]. Moreover, alterations in the lipid composition of cellular membranes may influence proteolytic processing of AβPP and increase the release of Alzheimer’s amyloid beta-peptide from membranes [115].

In addition, Aβ peptide inhibits protein influx in the mitochondria, resulting in mutation of mitochondrial DNA (mtDNA), aggravating therefore mitochondrial dysfunction and disintegration eventually [116]. Experimental studies, on the other hand, revealed that the soluble form of Aβ peptide causes a reduced mitochondrial membrane potential (MMP) and energy production [117].

Mitochondrial dysfunction on the other hand may play an important role for enhancing the neurotoxicity of the Aβ peptide in AD, aggravating furthermore the oxidative stress. Oxidative stress is reasonably associated with amyloid β peptide accumulation in the neocortex [118], a fact which plays a crucial role in the pathogenesis of Alzheimer’s disease, inducing alterations to the cytoplasm of sensitive cells [119] by increasing reactive oxygen species (ROS) production [120]. This condition may cause further mitochondrial dysfunction, since the lack of histones in mitochondrial DNA makes them particularly vulnerable to oxidative stress [121, 122].

It is important that morphological alterations of the mitochondria in AD are observed in areas of the brain with minimal Alzheimer’s pathology, such as in the cerebellum, the hypothalamus and the mammillary bodies [123] suggesting that they are independent of the accumulation of neurofibrillary tangles and neuritic plaques.

It is well known that shape and the size of the mitochondria are highly variable [124], since they undergo continual fission and fusion, which are necessary for cell survival and harmonious adaptation to changing conditions [125] and are related, at the same time, with the processes of biogenesis [126] and the mitophagy [127].

In addition, mitochondrial morphology is sometimes controlled by the cytoskeleton, namely the neurofilaments and the microtubules [128]. The change of the shape of the mitochondria occurs mostly during their course through axons, dendrites and synaptic terminals via anterograde transport [129].

Many proteins are also important for the mitochondrial morphological integrity and for binding to the cytoskeletal components [130]. Porin is a protein in the outer membrane of the mitochondria that forms voltage-dependent anionic channels, between the mitochondrial inter membrane space and the cytosol [131]. Porin may play crucial role in binding to cytoskeleton [132], because porin-rich domains mostly contain binding sites for MAP2. In addition, recent evidence suggest that amyloid β increases the contact points between endoplasmic reticulum and mitochondria, a phenomenon that occurs in cellular stress, which usually increases ER-mitochondrial coupling [133].

Normally, approximately one-third of the mitochondria are in motion along with microtubules and actin filaments [128, 134], transported to regions where energy requirement is particularly high. The number of the mitochondria is adjusted, according to the requirement of energy by the cell. It is reasonable that the dysfunctional mitochondria may undergo mitophagy [135], a fact which is associated with neurodegeneration [136] and many devastating conditions of the brain.

Morphometric studies of the mitochondria in non-nerve cells in AD revealed a significant reduction in mitochondrial density in endothelial cells [137] as well as in fibroblasts and other cells obtained from patients with AD [138]. Mitochondria from fibroblasts grown in tissue culture from skin samples taken during autopsy of patients of AD, took significantly less calcium than did mitochondria of fibroblasts from age matched normal controls, suggesting that Alzheimer’s fibroblast mitochondria have impaired calcium transport processes and showed increased sensitivity to oxygenic free radicals [139].

The most dramatic morphological alterations of the mitochondria are seen in dendritic profiles and the synaptic terminals. The defective mitochondria in AD neurons may not supply adequate levels of adenosine triphosphate (ATP), which is very important factor at the synaptic level for normal neural communication. The low levels of cellular ATP at nerve terminals may lead to the loss of synapses and considerable decline of synaptic function, causing serious cognitive impairment and profound dementia ultimately.

Mitochondrial alterations in AD are observed also in astrocytes, although mitochondrial dynamics of astrocytes are not yet extensively studied. Astrocytes participate in the degradation of neuronal mitochondria via the process of transmitophagy [140] that occurs following internalization of axonal mitochondria by astrocytic processes, which normally contain very small mitochondria [141]. Astrocytic alterations have been described in cases of familial Alzheimer’s disease [142] as well as in advanced cased of sporadic type of Alzheimer’s disease [143], demonstrating evidence of the toxicity of the Aβ peptide [144]. The mitochondrial alterations of the astrocytes in early case of Alzheimer’s disease enhance the noxious role of the Aβ peptide on the function and the integrity of the astrocytes [145] with serious implications on neuroprotection [146] due to the increased excitotoxicity, which would be a reasonable consequence of the disruption of glutamate/GABA-glutamine cycle [147].

In all of the cases, it was noticed that the morphological alterations of mitochondria in neurons and astrocytes are frequently associated with the fragmentation of Golgi apparatus and the decrease of the vesicles in cis- and trans-Golgi network [1956]. The morphological alterations of the mitochondria and the fragmentation of Golgi complex coincide with the dendritic and synaptic pathology in early cases of Alzheimer’s disease [22, 148].

Understanding the important role the mitochondrial factor plays in the etiopathogenetic cascade of Alzheimer’s disease [13], new therapeutic strategies aim at protecting the mitochondria [149] and preventing oxidative stress, calcium imbalance and eventual apoptosis might be beneficial in the treatment of early cases of AD.

Advertisement

5. Conclusions

The study in electron microscopy of various areas of the cerebral cortex, including the prefrontal area, the superior parietal lobe, the occipital pole, the visual cortex and the Hessl gyri of the temporal neocortex, and various areas of the cerebellar cortex, the hypothalamus, the mammillary bodies and the medial geniculate body in early cases of Alzheimer’s disease, revealed serious morphological alterations of the mitochondria in the perikaryon, the dendritic branches the axons and the synapses.

The most dramatic alteration of the mitochondrial morphology was observed in the dendritic profiles, the dendritic spines and the synapses, associated with poverty of synaptic vesicles and accumulation of multi vesicular bodies.

The morphological alterations of the mitochondria were not dependent on the typical Alzheimer’s pathology, since they were seen in areas with minimal β amyloid aggregations and no neurofibrillary tangles, such as the cerebellum, the hypothalamus and the visual cortex, suggesting that the mitochondrial alterations are not the direct consequence of amyloid toxicity.

Mitochondrial alterations were also seen in astrocytes and oligodendrocytes frequently in association with dilatation of the cisternae of the smooth endoplasmic reticulum and Golgi complex.

The mitochondria alterations induce a substantial decline of energy supply to neuronal processes, affecting the protein trafficking, the membrane dynamics as well as the synaptic activity, resulting in gradual synaptic and dendritic degeneration and in neuronal apoptosis eventually.

Mitochondria are strategic points in the pathogenetic field of Alzheimer’s disease. New therapeutic strategies aiming at protecting the mitochondria, increasing the energy supply and preventing oxidative stress and calcium imbalance, might be beneficial in the treatment of early cases of AD.

Advertisement

Conflict of interest

No conflict of interest.

Advertisement

Nomenclature and abbreviations

ADAlzheimer’s disease

References

  1. 1.Reitz C, Mayeux R. Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers. Biochemical Pharmacology. 2014;88:640-651
  2. 2.Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: Few candidates, frequent failures. Alzheimer’s Research & Therapy. 2014;6:37
  3. 3.Schelke MW, Attia P, Palenchar D, Kaplan B, Mureb M, Ganzer CA, et al. Mechanisms of risk reduction in the clinical practice of Alzheimer’s disease prevention. Frontiers in Aging Neuroscience. 2018;10:96
  4. 4.Baloyannis SJ. Neuropathology of Dementia. Aristotelian University of Thessaloniki; 1993
  5. 5.Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimer’s & Dementia. 2010;6:158-194
  6. 6.Wisniewski HM, Wegiel J, Kotula L. Some neuropathological aspects of Alzheimer’s disease and its relevance to other disciplines. Neuropathology and Applied Neurobiology. 1996;22:3-11
  7. 7.Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathologica. 2009;118:5-36
  8. 8.Baloyannis S, Costa V, Arnaoutoglou A, Arnaoutoglou H. Synaptic alterations in the molecular layer of the cerebellum in Alzheimer’s disease. Neuropathology and Applied Neurobiology. 1996;22:78-79
  9. 9.Baloyannis SJ, Manolidis SL, Manolidis LS. Synaptic alterations in the vestibule-cerebellar system in Alzheimer’s disease-a Golgi and electron microscope study. Acta Oto-Laryngologica. 2000;120:247-250
  10. 10.Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002;298:789-791
  11. 11.Poirel O, Mella S, Videau C, Ramet L, Davoli MA, Herzog E, et al. Moderate decline in select synaptic markers in the prefrontal cortex (BA9) of patients with Alzheimer’s disease at various cognitive stages. Scientific Reports. 2018;8:938
  12. 12.Baloyannis SJ, Costa V, Michmizos D. Mitochondrial alterations in Alzheimer’s disease. American Journal of Alzheimer’s Disease and Other Dementias. 2004;19:89-93
  13. 13.Baloyannis SJ. Mitochondria: Strategic point in the field of Alzheimer’s disease. Journal of Alzheimers and Neurodegenerative Diseases. 2016;2:004
  14. 14.Iqbal K, Liu F, Gong CX, Grundke-Iqbal I. Tau in Alzheimer disease and related tauopathies. Current Alzheimer Research. 2010;7:656-664
  15. 15.Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004;430:631-639
  16. 16.Baloyannis SJ, Baloyannis IS. The vascular factor in Alzheimer’s disease: A study in Golgi technique and electron microscopy. Journal of the Neurological Sciences. 2012;322:117-121
  17. 17.Dickson DM. The pathogenesis of senile plaques. Journal of Neuropathology and Experimental Neurology. 1997;56:321-339
  18. 18.Gandy S. The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. The Journal of Clinical Investigation. 2005;115:1121-1129
  19. 19.Baloyannis S. The Golgi apparatus of Purkinje cells in Alzheimer’s disease. In: Bohl J, editor. Neuropathology Back to the Roots. Aachen, Germany: Shaker Vertag; 2002. pp. 1-10
  20. 20.Hirai K, Aliev G, Nunomura A, et al. Mitochondrial abnormalities in Alzheimer’s disease. The Journal of Neuroscience. 2001;21:3017-3023
  21. 21.Baloyannis SJ, Baloyannis JS. Mitochondrial alterations in Alzheimer’s disease. Neurobiology of Aging. 2004;25:405-406
  22. 22.Baloyannis SJ. Mitochondria are related to synaptic pathology in Alzheimer’s disease. International Journal of Alzheimer’s Disease. 2011;2011:305395. DOI: 10.4061/2011/305395
  23. 23.Cummings JL, Vinters HV, Cole GM, Khachaturian ZS. Alzheimer’s disease etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology. 1998;51(1 Suppl 1):S2-S17
  24. 24.Weinstein JD. Alzheimer’s disease: Multiple causes requiring multiple therapies. Acta Scientific Medical Sciences. 2018;2:16-20
  25. 25.Lendon CL, Ashall F, Goate AM. Exploring the etiology of Alzheimer disease using molecular genetics. Journal of the American Medical Association. 1997;277:825-831
  26. 26.Breitner JC. Alzheimer’s disease: Genetic theories of etiology. In: Handbook of Psychopharmacology. Boston, MA: Springer; 1988. pp. 207-235
  27. 27.Selkoe DJ. Alzheimer’s disease: Genes, proteins, and therapy. Physiological Reviews. 2001;81:741-766
  28. 28.Mravec B, Horvathova L, Padova A. Brain under stress and Alzheimer’s disease. Cellular and Molecular Neurobiology. 2018;38:73-84
  29. 29.Rogers JO, Morrison JH. Quantitative morphology and regional and laminar distributions of senile plaques in Alzheimer’s disease. The Journal of Neuroscience. 1985;5:2801-2808
  30. 30.Sochocka M, Zwolinska K, Leszek J. The infectious etiology of Alzheimer’s disease. Current Neuropharmacology. 2017;15:996-1009
  31. 31.Jevtic S, Sengar AS, Salter MW, McLaurin J. The role of the immune system in Alzheimer disease: Etiology and treatment. Ageing Research Reviews. 2017;40:84-94
  32. 32.Carlsen EM, Rasmussen R. Protein networks in Alzheimer’s disease. Cell Systems. 2017;4:153-155
  33. 33.Santos CY, Snyder PJ, Wu WC, Zhang M, Echeverria A, Alber J. Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2017;7:69-87
  34. 34.Ning K, Chen B, Sun F, Hobel Z, Zhao L, Matloff W, et al. Alzheimer’s disease neuroimaging initiative. Classifying Alzheimer’s disease with brain imaging and genetic data using a neural network framework. Neurobiology of Aging. 2018;68:151-158
  35. 35.Bierer LM, Haroutunian V, Gabriel S, Knott PJ, Carlin LS, Purohit DP, et al. Neurochemical correlates of dementia severity in Alzheimer’s disease: Relative importance of the cholinergic deficits. Journal of Neurochemistry. 1995;64:749-760
  36. 36.Hampel H, Bürger K, Teipel SJ, Bokde AL, Zetterberg H, Blennow K. Core candidate neurochemical and imaging biomarkers of Alzheimer’s disease. Alzheimer’s & Dementia. 2008;4:38-48
  37. 37.Atwood CS, Huang X, Moir RD, Tanzi RE, Bush AI. Role of free radicals and metal ions in the pathogenesis of Alzheimer’s disease. In: Metal Ions in Biological Systems. Abingdon-on-Thames. Routledge; 2018. pp. 309-364
  38. 38.Murray HC, Swanson ME, Dieriks BV, Turner C, Faull RL, Curtis MA. Neurochemical characterization of PSA-NCAM+ cells in the human brain and phenotypic quantification in Alzheimer’s disease entorhinal cortex. Neuroscience. 2018;372:289-303
  39. 39.Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: Time, space and ‘wingmen’. Nature Neuroscience. 2015;18:800
  40. 40.Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Molecular Medicine. 2016;8:595-608
  41. 41.Manyevitch R, Protas M, Scarpiello S, Deliso M, Bass B, Nanajian A, et al. Evaluation of metabolic and synaptic dysfunction hypotheses of Alzheimer’s disease (AD): A meta-analysis of CSF markers. Current Alzheimer Research. 2018;15:164-181
  42. 42.Du X, Wang X, Geng M. Alzheimer’s disease hypothesis and related therapies. Translational Neurodegeneration. 2018;7(2):1-7
  43. 43.Kaufman SK, Del Tredici K, Thomas TL, Braak H, Diamond MI. Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART. Acta Neuropathologica. 2018;136:57-67
  44. 44.Salinaro AT, Pennisi M, Di Paola R, Scuto M, Crupi R, Cambria MT, et al. Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer’s disease and Alzheimer-linked pathologies: Modulation by nutritional mushrooms. Immunity & Ageing. 2018;15:8
  45. 45.Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain. 2018;141:1917-1933
  46. 46.Vergallo A, Giampietri L, Baldacci F, Volpi L, Chico L, Pagni C, et al. Oxidative stress assessment in Alzheimer’s disease: A clinic setting study. American Journal of Alzheimer’s Disease and Other Dementias. 2018;33:35-41
  47. 47.Baloyannis SJ. Brain capillaries in Alzheimer’s disease. Hellenic Journal of Nuclear Medicine. 2015;18:152
  48. 48.Di Marco LY, Venneri A, Farkas E, Evans PC, Marzo A, Frangi AF. Vascular dysfunction in the pathogenesis of Alzheimer’s disease—A review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiology of Disease. 2015;82:593-606
  49. 49.Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer’s disease. Journal of Neuroscience Research. 2017;95:943-972
  50. 50.Le Page A, Dupuis G, Frost EH, Larbi A, Pawelec G, Witkowski JM, et al. Role of the peripheral innate immune system in the development of Alzheimer’s disease. Experimental Gerontology. 2018;107:59-66
  51. 51.Takeda S, Morishita R. Diabetes and Alzheimer’s disease. In: Diabetes and Aging-related Complications. Singapore: Springer; 2018. pp. 101-111
  52. 52.Folch J, Ettcheto M, Busquets O, Sánchez-López E, Castro-Torres R, Verdaguer E, et al. The implication of the brain insulin receptor in late onset Alzheimer’s disease dementia. Pharmaceuticals. 2018;11:11. DOI: 10.3390/ph11010011
  53. 53.Baloyannis SJ. Mitochondrial alterations in Alzheimer’s disease. Journal of Alzheimer’s Disease. 2006;9:119-126
  54. 54.Swerdlow RH. Mitochondria and mitochondrial cascades in Alzheimer’s disease. Journal of Alzheimer’s Disease. 2018;62:1403-1416
  55. 55.Stieber A, Mourelatos Z, Gonatas NK. In Alzheimer’s disease the Golgi apparatus of a population of neurons without neurofibrillary tangles is fragmented and atrophic. The American Journal of Pathology. 1996;148:415-426
  56. 56.Baloyannis SJ. Golgi apparatus and protein trafficking in Alzheimer’s disease. Journal of Alzheimer’s Disease. 2014;42:S153-S162
  57. 57.Joshi G, Bekier MI, Wang Y. Golgi fragmentation in Alzheimer’s disease. Frontiers in Neuroscience. 2015;9:340. DOI: 10.3389/fnins.2015.00340
  58. 58.Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biology. 2018;14:450-464
  59. 59.Džinić T, Dencher NA. Oxygen concentration and oxidative stress modulate the influence of Alzheimer’s disease Aβ1-42 peptide on human cells. Oxidative Medicine and Cellular Longevity. 2018;2018:16. DOI: 10.1155/2018/7567959. Article ID: 7567959
  60. 60.Kametani F, Hasegawa M. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease. Frontiers in Neuroscience. 2018;12:25. DOI: 10.3389/fnins.2018.00025
  61. 61.Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2014;1842:1240-1247
  62. 62.Atamna H, Frey WH II. Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease. Mitochondrion. 2007;7:297-310
  63. 63.Du H, Guo L, Yan SS. Synaptic mitochondrial pathology in Alzheimer’s disease. Antioxidants and Redox Signaling. 2012;16:1467-1475
  64. 64.Bennett RE, Robbins AB, Hu M, Cao X, Betensky RA, Clark T, et al. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease. Proceedings of the National Academy of Sciences. 2018;115:E1289-E1298
  65. 65.Polverino A, Grimaldi M, Sorrentino P, Jacini F, D’Ursi AM, Sorrentino G. Effects of acetylcholine on β-amyloid-induced cPLA2 activation in the TB neuroectodermal cell line: Implications for the pathogenesis of Alzheimer’s disease. Cellular and Molecular Neurobiology. 2018;38:817-826
  66. 66.Iaccarino L, Tammewar G, Ayakta N, Baker SL, Bejanin A, Boxer AL, et al. Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer’s disease. NeuroImage: Clinical. 2018;17:452-464
  67. 67.Saraiva AA, Borges MM, Madeira MD, Tavares MA, Paula-Barbosa MM. Mitochondrial abnormalities in cortical dendrites from patients with Alzheimer’s disease. Journal of Submicroscopic Cytology. 1985;17:459-464
  68. 68.Li Z, Okamoto KI, Hayashi Y, Sheng M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell. 2004;119:873-887
  69. 69.Baloyannis SJ. Dendritic pathology in Alzheimer’s disease. Journal of the Neurological Sciences. 2009;283:153-157
  70. 70.McGeer EG, McGeer PL. Innate immunity in Alzheimer’s disease. Molecular Interventions. 2001;1:22-29
  71. 71.McGeer PL, McGeer EG. Inflammation, autotoxicity and Alzheimer disease. Neurobiology of Aging. 2001;22:799-809
  72. 72.Boza-Serrano A, Yang Y, Paulus A, Deierborg T. Innate immune alterations are elicited in microglial cells before plaque deposition in the Alzheimer’s disease mouse model 5xFAD. Scientific Reports. 2018;8:1550
  73. 73.Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Naj AC, Boland A, et al. Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing. bioRxiv. 2018:294629
  74. 74.Lewis MR, Lewis WH. Mitochondria in tissue culture. Science. 1914;39:330-333
  75. 75.Harman D. The biologic clock: The mitochondria? Journal of the American Geriatrics Society. 1972;20:145-147
  76. 76.Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194-1217
  77. 77.Hughes BG, Hekimi S. A mild impairment of mitochondrial electron transport has sex-specific effects on lifespan and aging in mice. PLoS One. 2011;6:e26116
  78. 78.Beal M, Hyman B, Koroshetz W. Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends in Neurosciences. 1993;16:125-131
  79. 79.Mentzies F, Cookson M, Taylor R, et al. Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. Brain. 2002;125:1522-1533
  80. 80.Perry G, Nunomura A, Hirai K, Takeda A, Aliev G, Smith M. Oxidative damage in Alzheimer’s disease: The metabolic dimention. International Journal of Developmental Neuroscience. 2000;18:417-421
  81. 81.Edland SD, Silverman JM, Peskind ER, Tsuang D, Wijsman E, Morris JC. Increased risk of dementia in mothers of Alzheimer’s disease cases: Evidence for maternal inheritance. Neurology. 1996;47:254-256
  82. 82.Bassett SS, Avramopoulos D, Fallin D. Evidence for parent of origin effect in late- onset Alzheimer disease. American Journal of Medical Genetics. 2002;114:679-686
  83. 83.Debette S, Wolf PA, Beiser A, Au R, Himali JJ, Pikula A, et al. Association of parental dementia with cognitive and brain MRI measures in middle-aged adults. Neurology. 2009;73:2071-2078
  84. 84.Morris JC, Heyman A, Mohs RC, Hughes JP, Van Belle G, Fillenbaum GD, et al. The consortium to establish a registry for Alzheimer’s disease (CERAD): I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology. 1989;39:1159-1165
  85. 85.Dubois B, Feldman HH, Jacova C, DeKosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer’s disease: Revising the NINCDS-ADRDA criteria. The Lancet Neurology. 2007;6:734-746
  86. 86.McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia. 2011;7:263-269
  87. 87.Schindler SE, Jasielec MS, Weng H, Hassenstab JJ, Grober E, McCue LM, et al. Neuropsychological measures that detect early impairment and decline in preclinical Alzheimer disease. Neurobiology of Aging. 2017;56:25-32
  88. 88.Tombaugh TN, McIntyre NJ. The mini-mental state examination: A comprehensive review. Journal of the American Geriatrics Society. 1992;40:922-935
  89. 89.Arevalo-Rodriguez I, Smailagic N, I Figuls MR, Ciapponi A, Sanchez-Perez E, Giannakou A, et al. Mini-mental state examination (MMSE) for the detection of Alzheimer’s disease and other dementias in people with mild cognitive impairment (MCI). Cochrane Database of Systematic Reviews. 2015;5(3):CD010783
  90. 90.Mattis S. Dementia Rating Scale Professional Manual, Psychological Assessment Resources; Odessa, Fla, USA; 1988
  91. 91.Dean PM, Cerhan JH. Correction for a potentially biased item on the mattis dementia rating scale. American Journal of Alzheimer’s Disease and Other Dementias. 2013;28:734-737. DOI: 10.1177/1533317513504610
  92. 92.Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. The American Journal of Psychiatry. 1984;141:1356-1364
  93. 93.Harrison JC, Minassian SL, Jenkins L, et al. A neuropsychological test battery for use in Alzheimer disease clinical trials. Archives of Neurology. 2007;64:1323-1329
  94. 94.Hollocks MJ, Brookes RL, Morris RG, Markus HS. The Brief Memory and Executive Test (BMET): A cognitive screening tool to detect and differentiate vascular cognitive impairment and Alzheimer’s disease. International Journal of Geriatric Psychiatry. 2018;33:e273-e279
  95. 95.Kogure D, Matsuda H, Ohnishi T, Asada T, Uno M, Kunihiro T, et al. Longitudinal evaluation of early Alzheimer’s disease using brain perfusion SPECT. Journal of Nuclear Medicine. 2000;41:1155-1162
  96. 96.Sotelo C, Hillman DE, Zamora AJ, Llinás R. Climbing fiber deafferentation: Its action on Purkinje cell dendritic spines. Brain Research. 1975;98:574-581
  97. 97.Baloyannis SJ, Mavroudis I, Mitilineos D, Baloyannis IS, Costa VG. The hypothalamus in Alzheimer’s disease: A Golgi and electron microscope study. American Journal of Alzheimer’s Disease and Other Dementias. 2015;30:478-487
  98. 98.Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Annals of Neurology. 1995;38:357-366
  99. 99.Cardoso S, Proenca M, Santos S, Santana I, Oliveira C. Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiology of Aging. 2004;25:105-110
  100. 100.Fisar Z, Hroudová J, Hansíková H, Lelková P, Wenchich L, Jirák R, et al. Mitochondrial respiration in the platelets of patients with Alzheimer’s disease. Current Alzheimer Research. 2016;13:930-941
  101. 101.Mutisaya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. Journal of Neurochemistry. 1994;63:2179-2184
  102. 102.Davis RE, Miller S, Herrnstadt C, et al. Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America. 1997;94:4526-4531
  103. 103.Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E. Mitochondria, oxidative stress and neurodegeneration. Journal of the Neurological Sciences. 2012;322:254-262
  104. 104.Mancuso M, Coppede F, Migliore L, Siciliano G, Murri L. Mitochondrial dysfunction, oxidative stress and neurodegeneration. Journal of Alzheimer’s Disease. 2006;10:59-73
  105. 105.Radi E, Formichi P, Battisti C, Federico A. Apoptosis and oxidative stress in neurodegenerative diseases. Journal of Alzheimer’s Disease. 2014;42(Suppl 3):S125-S152
  106. 106.Butterfield DA. The 2013 SFRBM discovery award: Selected discoveries from the butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment. Free Radical Biology & Medicine. 2014;74:157-174
  107. 107.Hamanaka RB, Chandel NS. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends in Biochemical Sciences. 2010;35:505-513
  108. 108.Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxidative Medicine and Cellular Longevity. 2013;2013:316523
  109. 109.Alonso AD, Grundke-Iqbal I, Iqbal K. Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nature Medicine. 1996;2:783-787
  110. 110.Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, et al. S-Nitrosylation of Drp 1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009;324:102-105
  111. 111.Anandatheerthavarada HK, Biswas G, Robin M-A, Avadhani NG. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. The Journal of Cell Biology. 2003;161:41-54
  112. 112.De Strooper B, Scorrano L. Close encounter: Mitochondria, endoplasmic reticulum and Alzheimer’s disease. The EMBO Journal. 2012;31:4095-4097
  113. 113.Du H, Guo L, Fang F, et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nature Medicine. 2008;14:1097-1105
  114. 114.Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, et al. ABAD directly links Aβ to mitochondrial toxicity in Alzheimer’s disease. Science. 2004;304:448-452
  115. 115.Lemkul JA, Bevan DR. Lipid composition influences the release of Alzheimer’s amyloid beta-peptide from membranes. Protein Science. 2011;20:1530-1545
  116. 116.Lakatos A, Derbeneva O, Younes D, Keator D, Bakken T, Lvova M, et al. Association between mitochondrial DNA variations and Alzheimer’s disease in the ADNI cohort. Neurobiology of Aging. 2010;31:1355-1363
  117. 117.Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, et al. Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:20057-20062
  118. 118.Morais Cardoso S, Swerdlow R, Oliveira C. Induction of cytochrome c-mediated apoptosis by amyloid beta 25-35 requires functional mitochondria. Brain Research. 2002;931:117-125
  119. 119.Lustbader J, Cirilli M, Lin C, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science. 2004;304:448-453
  120. 120.Sheehan J, Swerdlow R, Miller S, et al. Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer’s disease. The Journal of Neuroscience. 1997;17:4612-4622
  121. 121.Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Annals of Neurology. 1994;36:747-751
  122. 122.Wang J, Xiong S, Xie C, et al. Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer’s disease. Journal of Neurochemistry. 2005;93:953-962
  123. 123.Baloyannis SJ, Mavroudis I, Baloyannis IS, Costa VG. Mammillary bodies in Alzheimer’s disease: A Golgi and electron microscope study. American Journal of Alzheimer’s Disease and Other Dementias. 2016;31:247-256
  124. 124.Bereiter-Hahn J, Vöth M. Dynamics of mitochondria in living cells: Shape changes, dislocations, fusion, and fission of mitochondria. Microscopy Research and Technique. 1994;27:198-219
  125. 125.Youle RJ, van der Bliek AM. Mitochondrial fission, fusion and stress. Science. 2012;337:1062-1065
  126. 126.Onyango IG, Lu J, Rodova M, Lezi E, Crafter AB, Swerdlow RH. Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochimica et Biophysica Acta. 2010;1802:228-234
  127. 127.Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Archives of Biochemistry and Biophysics. 2007;462:245-253
  128. 128.Leterrier JF, Rusakov DA, Nelson BD, Linden M. Interactions between brain mitochondria and cytoskeleton: Evidence for specialized outer membrane domains involved in the association of cytoskeleton-associated proteins to mitochondria in situ and in vitro. Microscopy Research and Technique. 1994;27:233-261
  129. 129.Hollenbeck PJ, Saxton WM. The axonal transport of mitochondria. Journal of Cell Science. 2005;118:5411-5419
  130. 130.Truscott K, Pfanner N, Voos W. Transport of proteins into mitochondria. Reviews of Physiology, Biochemistry and Pharmacology. 2001;143:81-136
  131. 131.Lauterwasser J, Todt F, Zerbes RM, Nguyen TN, Craigen W, Lazarou M, et al. The porin VDAC2 is the mitochondrial platform for Bax retrotranslocation. Scientific Reports. 2016;6:32994
  132. 132.Wagner O, Lifshitz J, Janmey P, et al. Mechanisms of mitochondria-neurofilament interactions. The Journal of Neuroscience. 2003;23:9046-9058
  133. 133.Bravo R, Vicencio JM, Parra V, et al. Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress. Journal of Cell Science. 2011;124:2143-2152
  134. 134.Schwarz TL. Mitochondrial trafficking in neurons. Cold Spring Harbor Perspectives in Biology. 2013;5(6)
  135. 135.Scherz-Shouval R, Elazar Z. Regulation of autophagy by ROS: Physiology and pathology. Trends in Biochemical Sciences. 2011;36:30-38
  136. 136.Karbowski M, Neutzner A. Neurodegeneration as a consequence of failed mitochondrial maintenance. Acta Neuropathologica. 2012;123:157-171
  137. 137.Stewart P, Hayakawa K, Akers M, Vinters H. A morphometric study of the blood-brain barrier in Alzheimer’s disease. Laboratory Investigation. 1992;67:734-742
  138. 138.Blass J, Fheu R, Gibson G. Inheritent abnormalities in energy metabolism in Alzheimer’s disease: Interaction with cerebrovascular compromise. Annals of the New York Academy of Sciences. 2000;903:204-221
  139. 139.Peterson C, Golman JE. Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer donors. Proceedings of the National Academy of Sciences of the United States of America. 1986;83:2758-2762
  140. 140.Davis CH, Kim KY, Bushong EA, et al. Transcellular degradation of axonal mitochondria. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(26):9633-9638
  141. 141.Derouiche A, Haseleu J, Korf HW. Fine astrocyte processes contain very small mitochondria: Glial oxidative capability may fuel transmitter metabolism. Neurochemical Research. 2015;40(12):2402-2413
  142. 142.Rodríguez-Arellano JJ, Parpura V, Zorec R, et al. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience. 2016;323:170-182
  143. 143.Osborn LM, Kamphuis W, Wadman WJ, et al. Astrogliosis: An integral player in the pathogenesis of Alzheimer’s disease. Progress in Neurobiology. 2016;144:121-141
  144. 144.Abramov AY, Canevari L, Duchen MR. Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. Journal of Neuroscience. 2004;24(2):565-575
  145. 145.Pagani L, Eckert A. Amyloid-Beta interaction with mitochondria. International Journal of Alzheimer’s Disease. 2011;2011:925050
  146. 146.Voloboueva LA, Suh SW, Swanson RA, et al. Inhibition of mitochondrial function in astrocytes: Implications for neuroprotection. Journal of Neurochemistry. 2007;102(4):1383-1394
  147. 147.Bak LK, Schousboe A, Waagepetersen HS. The glutamate/GABA-glutamine cycle: Aspects of transport, neurotransmitter homeostasis and ammonia transfer. Journal of Neurochemistry. 2006;98(3):641-653
  148. 148.Nakamura T, Lipton SA. Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases. Cell Death and Differentiation. 2011;18:1478-1486
  149. 149.Singh N, Ghosh KK. Recent advances in the antioxidant therapies for Alzheimer’s Disease: Emphasis on natural antioxidants. In: Pathology, Prevention and Therapeutics of Neurodegenerative Disease. Singapore: Springer; 2019. pp. 253-263

Written By

Stavros J. Baloyannis

Submitted: October 10th, 2018Reviewed: January 31st, 2019Published: September 25th, 2019