Alzheimer’s disease, Mitochondria, Golgi apparatus, Purkinje cells, Cerebellum, Ultrastructure, Morphometry, Oxidative stress

AD, Alzheimer’s Disease; mtDNA, mitochondrial DNA; CytOX, Cytochrome c Oxidase; ROS, Reactive Oxygen Species; APP, Amyloid Precursor Protein; AβPP, Amyloid-β Precursor Protein; ER, Endoplasmic Reticulum

Alzheimer’s disease (AD) is an insidiously progressive presenile and senile dementia of an un avoidable tragic outcome, affecting millions of humans, which became a serious medical challenge for aging population in our era, inducing at the same time many ethical, social and economic problems. The phenomenology of the disease is mostly characterized by profound memory loss, visuo-spatial disorientation, loss of professional skills, learning inability, language disturbances, mood and behavioral changes¹ and autonomic disorders, phenomena which appear increasingly as the disease advances, resulting in a vegetative state eventually.

The etiopathological background of the disease involves a substantial number of cellular and biochemical mechanisms, which co-operate progressively in plotting the clinical and morphological pattern of the disease. However, the real crucial causative factors remain still invisible, in spite of the persistent continuous augmentation of the research efforts.

The multiple genetic loci, associated with familial AD,² may plead in favor of its heterogeneity and support the idea that the clinical characters and the course of the disease are the eventual consequences of various metabolic, neurochemical and morphological alterations, based on a broad genetic background,³ on which aging and many environmental factors may contribute as triggering or additional potentiating agents. Moreover the increased risk of Alzheimer’s disease in sporadic cases, when a maternal relative is afflicted with the disease, advocates in favor of a maternally derived factor, which is related probably to mitochondrial DNA (mtDNA).

It is well established that the implication of amyloid-β peptide, AβPP and tau protein play a very important role in the pathogenesis of AD,⁴ without enlightening sufficiently the innermost pathological procedures. According to “amyloid cascade” hypothesis, amyloidogenesis, which is the production of the amyloid-β peptide (Aβ peptide), a cleavage product of the β-amyloid protein precursor (AβPP)^5-7 is the most possible causative component in both familial and sporadic types of AD, given that the elevated intra- or extracellular levels of Aβ oligomers protofibrils are believed to be of considerable pathogenic significance, due to their excessive neuronal and synaptic toxicity.^8,9 It is hypothesized that a chronic disequilibrium and instability between the production and clearance of amyloid-β peptide and its molecular misfolding may lead step by step to synaptic alterations and glial activation.¹⁰

From the neuropathological point of view, AD is mostly characterized by (a) selective neuronal loss, (b) marked synaptic loss, which play the most important role in the tragedy of the gradual decline of the mental capacities, (c) morphological mitochondrial abnormalities, (d) cytoskeletal alterations, (e) axonal dystrophy, (f) neuropil threads, (g) capillary changes, (h) blood brain barrier disruption and (i) inflammatory responses. Among them, the most characteristic morphological findings of definite diagnostic value, as real hallmarks of AD are (a) the tau pathology in the form of neurofibrillary tangles and (b) the extracellular extensive deposits of polymers of amyloid β peptide, in the form of neuritic plaques.

Morphological alterations of the neuronal organelles, concerning mainly microtubules, mitochondria, and Golgi apparatus affecting protein trafficking, have been described by histochemical techniques as well as in electron microscopy.¹¹

It must be emphasized that mitochondrial alterations are particularly prominent in neurons, which show loss of dendritic spines, abbreviation of the dendritic arbors and synaptic alterations.¹² In addition, many morphological alterations of AD, which are associated mostly with oxidative damage¹³ could be well linked to mitochondrial changes, since blockage of mitochondrial energy production shifts amyloid β-protein precursor metabolism to increased amyloidogenic activity.^14,15

Mitochondrial alterations, such as disruptions of mitochondrial function and mitochondrial dynamics, inducing considerable impairment of mitochondrial electron transport proteins, may be related to metabolic and energy deficiency, to alteration of neuronal signaling system¹⁶ in AD^17-19 and other neurodegenerative disorders,^20,21 in aging²² and in vascular lesions.²³ Τhe fact that mitochondrial abnormalities are observed also in neurons, which lack neurofibrillary tangles pleads in favor of the hypothesis that mitochondrial degeneration may be an early sign of Alzheimer’s pathology, associated mostly with dendritic alterations.²⁴

Mitochondrial abnormalities might be considered both as a cause and as an effect of the oxidative stress and calcium deregulation in AD,^25-27 in diabetes associated with AD²⁸ and other age-related neurodegenerative disorders.^29,30 The ultrastructural study of neurons in AD reveals an impressive polymorphism of mitochondria in the soma, the axons as well as in dendritic profiles and the synapses. Thus, the mitochondria demonstrate a wide variation of size and shape. A substantial number of them show disruption of the cristae, others incorporate osmiophilic material or show unusual polymorphism concerning the arrangement of the cristae, which sometimes have a concentric configuration or they are arranged in a parallel way to the long diameter of the organelle.^11,18,19 From the morphometric point of view the ellipsoid mitochondria in AD appear to have an average diameter of 250 to 510 nm and a mean axial ratio of 1.7± 0.2.¹⁹

It is well known that mitochondria are the only non-nuclear constituents of the cell with their own DNA (mtDNA) and the proper machinery for synthesizing RNA and proteins. They are instrumental for the energy equilibrium of the cell, given that they provide most of the energy for the cellular processes via oxidative phosphorylation of glucose, and by their involvement in other metabolic pathways. Their morphology is highly variable,³¹ sometimes controlled by cytoskeletal elements, especially by the neurofilament and the microtubules.³²

During the various neuronal processes approximately one third of the mitochondria are in motion along microtubules and actin filaments,^33,34 transported to regions where ATP consumption and necessity for energy are particularly high. The number of the mitochondria also varies, according to energy state of the cell.

Mitochondria and mtDNA³⁵ are very sensitive to oxidative damage and inversely mitochondrial alterations may induce or increase the existing oxidative stress, suggesting that there is an intimate and early association between oxidative stress and mitochondrial abnormalities. The combined effect of high calcium ions with oxidative stress in association with amyloid-β peptide overproduction may damage mitochondrial function³⁶ and may be implicated, as substantial causative factor, in apoptosis of many systems.^37-39

Some observations^40,41 advocate that increased oxidative damage, decrease in energy metabolism and altered cytochrome c oxidase (CytOX) activity are among the earliest events in AD emphasizing, therefore, the role that the dysfunction of the mitochondria and the oxidation of ion channels⁴² may play in the pathogenesis of majority of the devastating neurological diseases.^43,44 Reduced cytochrome oxidase activity has also been reported in platelets from patients suffered from AD⁴⁴ as well as in post mortem brain tissue, derived from patients suffered from AD.⁴⁵

It is important to be underlined that mitochondrial cytochrome c oxidase may be inhibited by a dimeric conformer of Aβ,⁴² a phenomenon which is copper dependent.^46,47 Oxidative stress, is reasonably associated with amyloid-β peptide accumulation in the neocortex,^48,49 a fact which plays a crucial role in the pathogenetic mechanisms of AD, inducing extensive damage to the cytoplasm of vulnerable cells⁵⁰ by increasing mitochondrial reactive oxygen species (ROS) production,⁵¹ which would cause further impairment of mitochondrial function,⁵² since the lack of histones in mitochondrial DNA renders them a vulnerable target to oxidative stress, being more sensitive to oxidation than the nuclear DNA.^53,54

Mitochondrial changes are also clearly associated with the over expression of the amyloid precursor protein (APP),⁵⁵ the increase of amyloid-β, which may inhibit degradation of pre­-sequence peptides by PreP, resulting in accumulation of mitochondrial pre-proteins and processing intermediates, inducing various mitochondrial dysfunctions.⁵⁶ Phosphorylated tau protein (PHF-1 epitope) may also potentiate the Aβ-induced mitochondrial injury⁵⁷ or the expression of the APP751 form in cultured cells.⁵⁸

It is well documented that generation of amyloid-β peptide may occur in the endoplasmic reticulum (ER), the Golgi apparatus, the lysosomes as well as on the cell surface,^59,60 been accumulated in the endosomes, the lysosomes, the multivesicular bodies⁶¹ and the mitochondria.⁶²

In AD intraneuronal amyloid precursor protein and amyloid-β peptide are mostly localized to mitochondria.⁶² Mitochondrial uptake of amyloid-β peptide is mediated by the translocase, which is located on the outer mitochondrial membrane (TOM import machinery).⁶³ The binding site for amyloid beta has been identified in the matrix space of the mitochondria, as alcohol dehydrogenase (ABAD), which participates in the metabolism of aldehydes and its deficiency may be involved in the generation of oxidative radicals and in mitochondrial toxicity.⁶⁴ Amyloid-β peptide may also induce mitochondrial dysfunctions by interaction with cyclophilin D, which is a subunit of the mitochondrial permeability transition pore.⁶⁵ AβPP cleaved by mitochondrial γ-secretase⁶⁶ is usually in a transmembrane-arrested orientation in the mitochondria, in contact with the mitochondrial translocation complexes.⁶⁷ In addition, alterations in the lipid composition of cellular membranes may influence the proteolytic processing of AβPP and increase the release of Alzheimer’s amyloid β-peptide from membranes.⁶⁸

Mitochondrial interactions and interconnections with neurofilament and microtubules have been described at the level of electron microscopy as well as in fluorescence microscopy, dynamic light scattering, atomic force microscopy and sedimentation assays,⁶⁹ which clarify the substantial role that mitochondria may play in plotting the profile of morphological alterations in AD.^70-72

Morphometric studies of the mitochondria in non-nerve cells in AD revealed a significant reduction in mitochondria density in endothelial cells of brain capillaries^73,74 as well as in fibroblasts and other cells obtained from patients suffered from AD. Mitochondria from fibroblasts grown in tissue culture from skin samples of AD patients taken at autopsy, take up significantly less calcium than do fibroblast mitochondria from age matched normal controls, suggesting that fibroblast mitochondria in AD have impaired calcium transport processes and show increased sensitivity to oxygen free radicals.⁷⁵ It is important to emphasize that the mitochondrial genome plays an essential role in risk for AD and maternal family history is associated with AD biomarkers.^76-78 Many protein systems are also essential in mitochondrial morphological integrity and in binding to the cytoskeleton.^79,80 Mitochondrial porin is an outer-membrane protein that forms regulated channels (Voltage Dependent Anionic Channels) between the mitochondrial inter membrane space and the cytosol. Porin may play an important role in binding to neurofilament and microtubules,⁸⁰ since porin rich domains contain most of the binding sites for MAP2. In addition recent evidence suggest that amyloid-β peptide increases the contact points between endoplasmic reticulum and mitochondria, a phenomenon that occurs in cellular stress,⁸¹ which usually increases ER–mitochondrial coupling.⁸²

On the basis of the substantial role that mitochondrial pathology⁸³ and mitochondrial genetic defects^84-87 seems to play in the pathogenetic cascade of AD^15,88 new strategies inducing protection to mitochondria by inhibition of mitochondrial β-oxidation,^89-92 inhibition of ERK-DLP1 signaling and mitochondrial division,⁹³ regulating calcium trafficking in the endoplasmic reticulum or via mitochondria⁹⁴ and controlling mitochondrial calcium uptake.^95,96 by the administration of efficient antioxidant factors and natural antioxidants.⁹⁷ or using nanotechnology.⁹⁸ and supporting the neuroplasticity.⁹⁹ may be introduced in the treatment of early cases of Alzheimer’s disease.

None.

None.

1. Vida S, Des Rosiers P, Carrier L, et al. Prevalence of depression in Alzheimer’s disease and validity of Research Diagnostic Criteria. J Geriatr Psychiatry Neurol. 1994;7(4):238–244.
2. Price DL, Sisodia SS. Mutant genes in familial Alzheimer's disease and transgenic models. Annu Rev Neurosci. 1998;21:479–505.
3. Tanzi RE. A genetic dichotomy model for the inheritance of Alzheimer's disease and common age–related disorders. J Clin Invest. 1999;104(9):1175–1179.
4. Mokhtar SH, Bakhuraysah MM, Cram DS, et al. The Beta–amyloid protein of Alzheimer's disease: communication breakdown by modifying the neuronal cytoskeleton. Int J Alzheimers Dis. 2013;2013:910502.
5. Tanzi RE, Betram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell. 2005;120(4):545–555.
6. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–356.
7. Walsh DM, Selkoe DJ. A beta oligomers – a decade of discovery. J Neurochem. 2007;101(5):1172–1184.
8. Shankar GM, Li S, Mehta TH, et al. Amyloid–beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008;14(8):837–842.
9. Demuro A, Parker I. Cytotoxicity of intracellular aβ42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate. J Neurosci. 2013;33(9):3824–3833.
10. Selkoe DJ. Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol. 2004;6(11):1054–1061.
11. Baloyannis SJ. Golgi apparatus and protein trafficking in Alzheimer's disease. J Alzheimers Dis. 2014;42(0):S153–S162.
12. Baloyannis SJ. Mitochondria are related to synaptic pathology in Alzheimer's disease. Int J Alzheimers Dis. 2011;2011:305395.
13. Perry G, Nunomura A, Hirai K, et al. Oxidative damage in Alzheimer’s disease: The metabolic dimention. Int J Dev Neurosci. 2000;18(4–5):417–421.
14. Butterfield DA, Drake J, Pocernich C, et al. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta–peptide. Trends Mol Med. 2001;7(12):548–554.
15. Swerdlow RH, Burns JM, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis. J Alzheimers Dis. 201020(Suppl 2):S265–S279.
16. van Vliet AR, Verfaillie T, Agostinis P. New functions of mitochondria associated membranes in cellular signaling. Biochim Biophys Acta. 2014;1843(10):2253–2262.
17. Ferrer I. Altered mitochondria, energy metabolism, voltage dependent anion channel, and lipid rafts converge to exhaust neurons in Alzheimer’s disease. J Bioenerg Biomembr. 2009;41(5):425–431.
18. Baloyannis S, Costa V, Michmizos D. Mitochondrial alterations in Alzheimer’s Disease, Am J Alzheimers Dis Other Demen. 200419(2):89–93.
19. Baloyannis SJ. Mitochondrial alterations in Alzheimer's disease. J Alzheimers Dis. 2006;9(2):119–126.
20. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60(5):748–766.
21. Mizuno Y, Ikebe S, Hattori N, et al. Role of mitochondria in the etiology and pathogenesis of Parkinson’s disease. Biochim Biophys Acta. 1995;1271(1):265–274.
22. Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA. 1994;91(23):10771–10778.
23. Aliev G, Smith MA, Seyidov D, et al. The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer’s disease. Brain Pathol. 2002;12(1):21–35.
24. Baloyannis SJ. Dendritic pathology in Alzheimer's disease. J Neurol Sci. 2009;283(1–2):153–157.
25. Adam–Vizi V, Starkov AA. Calcium and mitochondrial reactive oxygen species generation: how to read the facts. J Alzheimers Dis. 201020(Suppl 2):S413–S426.
26. Berridge MJ. Calcium hypothesis of Alzheimer's disease. Pflugers Arch. 2010;459(3):441–449.
27. Di Carlo M, Giacomazza D, Picone P, et al. Are oxidative stress and mitochondrial dysfunctionthe key players in the neurodegenerative diseases? Free Radic Res. 2012;46(11):1327–1338.
28. Lozanoa L, Lara–Lemusb R, Zentenoa E, et al. The mitochondrial O–linked N–acetylglucosamine transferase (mOGT) in the diabetic patient could be the initial trigger to develop Alzheimer disease. Exp Gerontol. 2014;58C:198–202.
29. Quintanilla RA, Jin YN, von Bernhardi R, et al. Mitochondrial permeability transition pore induces mitochondria injury in Huntington disease. Mol Neurodegen. 2013;8:45.
30. MeloA, Monteiro L, Lima RM, et al. Oxidative stress in neurodegenerative diseases: Mechanisms and therapeutic perspectives. Oxid Med Cell Longev. 2011;2011:467180.
31. Bereiter–Hahn J, Voth M. Dynamic of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech. 1994;27(3):198–219.
32. Krendel M, Sgourdas G, Bonder EM. Disassembly of actin filaments leads to increased rate and frequency of mitochondria movements along microtubules. Cell Motil Cytoskeleton. 1998;40(4):368–378.
33. Leterrier J, Rusakov DA, Nelson BD, et al. 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. Microsc Res Tech. 1994;27(3):233–261.
34. Schwarz TL. Mitochondrial trafficking in neurons. Cold Spring Harbor Perspect Biol. 2013;5(6).
35. Margineantu DH, Cox W, Sundell L, et al. Cell cycle dependent morphology changes and associated mtDNA redistribution in mitochondria of human cell lines. Mitochondrion. 2002;1(5):425–435.
36. Wang X, Su B, Siedlak SL, et al. Amyloid–𝛽 overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A. 2008;105(49):19318–19323.
37. Duchen MR. Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signaling and cell death. J Physiol. 1999;516(pt 1):1–17.
38. Berridge MJ. Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia. Prion. 2013;7(1):2–13.
39. Caroppi P, Sinibaldi F, Fiorucci L, et al. Apoptosis and human diseases: Mitochondrion damage and lethal role of released cytochrome c as proapoptotic protein. Curr Med Chem. 2009;16(31):4058–4065.
40. Davis R, Miller S, Herrnstadt C, et al. Mutations in mitochondrial cytochrome c oxidase genes segregate with late onset Alzheimer disease. Proc Natl Acad Sci USA. 1997;94(9):4526–4531.
41. Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer’s disease. J Neuropathol Exp Neurol. 2001;60(8):759–767.
42. Lynch T, Cherny RA, Bush AI. Oxidative processes in Alzheimer’s disease: the role of Ab–metal interactions. Exp Gerontol. 2000;35(4):445–451.
43. De La Monte S, Luong T, Neely R, et al. Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease. Lab Invest. 2000;80(8):1323–1335.
44. Cardoso SM, Proenca MT, Santos S, et al. Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging. 2004;25(1):105–110.
45. Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem. 1994;63(6):2179–2184.
46. Deibel MA, Ehmann WD, Markesbery WR. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress. J Neurol Sci. 1996;143(1–2):137–142.
47. Crouch PJ, Blake R, Duce JA, et al. Copper–dependent inhibition of human cytochrome c oxidase by dimeric conformer of amyloid–1–42. J Neurosci. 200525(3):672–679.
48. Morais Cardoso S, Swerdlow R, Oliveira CR. Induction of cytochrome c–mediated apoptosis by amyloid beta 25–35 requires functional mitochondria. Brain Res. 2002931(2):117–125.
49. Moreira P, Santos MS, Moreno A, et al. Effect of amyloid beta–peptide on permeability transition pore: a comparative study. J Neurosci Res. 2002;69(2):257–267.
50. Pereira C, Santos M, Oliveira C. Involvement of oxidative stress on the impairment of energy metabolism induced by A beta peptides on PC12 cells: protection by antioxidants. Neurobiol Dis. 19996(3):209–219.
51. Sheehan J, Swerdlow RH, Miller SW, et al. Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer's disease. J Neurosci. 1997;17(12):4612–4622.
52. Arias C, Montiel T, Quiroz–Baez R, et al. beta–Amyloid neurotoxicity is exacerbated during glycolysis inhibition and mitochondrial impairment in the rat hippocampus in vivo and in isolated nerve terminals: implications for Alzheimer's disease. Exp Neurol. 2002;176(1):163–174.
53. Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol. 1994;36(5):747–751.
54. Wang J, Xiong S, Xie C, et al. Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease. J Neurochem. 2005;93(4):953–962.
55. Askanas V, McFerrin J, Baque S, et al. Transfer of beta–amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultured normal human muscle. Proc Natl Acad Sci USA. 1996;93(3):1314–1319.
56. Mossmann D, Vogtle FN, Taskin AA, et al. Amyloid–β peptide induces mitochondrial dysfunction by inhibition of preprotein maturation. Cell Metab. 2014;pii:S1550–4131(14)00332–5.
57. Quintanilla RA, von Bernhardib R, Godoyd JA, et al. Phosphorylated tau potentiates Aβ–induced mitochondrial damage in mature neurons. Neurobiol Dis. 2014;71C:260–269.
58. Grant SM, Shankar SL, Chalmers–Redman RM, et al. Mitochondrial abnormalities in neuroectodermal cells stably expressing human amyloid precursor protein (hAPP751). Neuro Report. 1999;10(1):41–46.
59. Cook D, Forman M, Sung J, et al. A beta(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med. 1997;3(9):1021–1023.
60. Greenfield J, Tsai J, Gouras GK, et al. Endoplasmic reticulum and trans–Golgi network generate distinct populations of Alzheimer beta–amyloid peptides. Proc Natl Acad Sci U S A. 1999;96(2):742–747.
61. Takahashi R, Milner T, Li F, et al. Intraneuronal Alzheimer A42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol. 2002;161(15):1869–1879.
62. Manczak M, Anekonda TS, Henson E, et al. Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 2006;15(9):1437–1449.
63. Hansson Petersen CA, Alikhani N, Behbahani H, et al. The amyloid beta peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci U S A. 2008;105(35):13145–13150.
64. Lustbader J, Cirilli M, Lin C, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science. 2004;304(5669):448–452.
65. Du H, Guo L, Fang F, et al. Cyclophilin D deficiency attenuates mitochondrialand neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med. 2008;14(10):1097–1105.
66. Pavlov PF, Wiehager B, Sakai J, et al. Mitochondrial γ–secretase participates in the metabolism of mitochondria–associated amyloid precursor protein. FASEB J. 2011;25(1):78–88.
67. Crompton M. Mitochondrial intermembrane junctional complexes and their role in cell death. J Physiol. 2000;529(pt 1):11–21.
68. Lemkul JA, Bevan DR. Lipid composition influences the release of Alzheimer’s amyloid beta–peptide from membranes. Protein Sci. 2011;20(9):1530–1545.
69. Mecocci P, Cherubini A, Beal M, et al. Altered mitochondrial membrane fluidity in AD brain. Neurosci Lett. 1996;207(2):129–132.
70. Baloyannis SJ, Manolidis SL, Manolidis LS. The acoustic cortex in Alzheimer’s disease. Acta Otolaryngol Suppl. 1992;494:1–13.
71. Baloyannis SJ. Recent progress of the golgi technique and electron microscopy to examine dendritic pathology in Alzheimer’s disease. Future Neurol. 2013;8(3):239–242.
72. Baloyannis S. The mossy fibres of the cerebellar cortex in Alzheimer΄s disease. An electron microscopy study. Neurosci. 1997;2:160–161.
73. Stewart PA, Hayakawa K, Akers MA, et  al. A morphometric study of the blood–brain barrier in Alzheimer's disease. Lab Invest. 1992;67(6):734–742.
74. Blass JP, Fheu RK, Gibson GE. Inheritent abnormalities in energy metabolism in Alzheimer’s disease: Interaction with cerebrovascular compromise. Ann NYA Cad Sci. 2000;903:204–221.
75. Peterson C, Golman JE. Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer donors. Proc Natl Acad Sci USA. 1986;83(8):2758–2762.
76. Ridge PG, Koop A, Maxwell TJ, et al. Mitochondrial haplotypes associated with biomarkers for Alzheimer ’s disease. PLoS One. 2013;8(9):e74158.
77. Honea RA, Vidoni ED, Swerdlow RH, et al.  Alzheimer’s Disease Neuroimaging Initiative. Maternal family history is associated with Alzheimer’s disease biomarkers. J Alzheimers Dis. 2012;31(3):659–668.
78. Martin LJ, Adams NA, Pan Y, et al. The mitochondrial permeability transition pore regulates nitric oxide–mediated apoptosis of neurons induced by target deprivation. J Neurosci. 2011;31(1):359–370.
79. Truscott K, Pfanner N, Voos W. Transport of proteins into mitochondria. Rev Physiol Biochem Pharmacol. 2001;143:81–136.
80. Wagner O, Lifshitz J, Janmey PA, et al. Mechanisms of mitochondria–neurofilament interactions. J Neurosci. 200323(27):9046–9058.
81. Bravo R, Vicencio JM, Parra V, et al. Increased ER–mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress. J Cell Sci. 2011;124 (pt 13):2143–2152.
82. Hedskog L, Pinho CM, Filadi R, et al. Modulation of the endoplasmic reticulum–mitochondria interface in Alzheimer’s disease and related models. Proc Natl Acad Sci U S A. 2013;110(19):7916–7921.
83. Reddy PH, Tripathi R, Troung Q, et al. Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: implications to mitochondria–targeted antioxidant therapeutics. Biochim Biophys Acta. 2012;1822(5):639–649.
84. Coskun PE, Beal MF, Wallace DC. Alzheimer’s brains harbor somaticmtDNA control–region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A. 2004;101(29):10726–10731.
85. Tranah GJ, Nalls MA, Katzman SM, et al. Mitochondrial DNA sequence variation associated with dementia and cognitive function in the elderly. J Alzheimers Dis. 2012;32(2):357–372.
86. Coto E, Gomez J, Alonso B, et al. Late–onset Alzheimer’s disease is associated with mitochondrial DNA 7028C/haplogroup H and D310 poly–C tract heteroplasmy. Neurogenetics. 2011;12(4):345–346.
87. Hudson G, Gomez–Duran A, Wilson IJ, et al. Recent mitochondrial DNA mutations increase the risk of developing common late–onset human diseases. PLoS Genet. 2014;10(5):e1004369.
88. Witte ME, Geurts JJ, de Vries HE, et al. Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion. 2010;10(5):411–418.
89. Chen CT, Trepanier MO, Hopperton KE, et al. Inhibiting mitochondrial β–oxidation selectively reduces levels of nonenzymatic oxidative polyunsaturated fatty acid metabolites in the brain. J Cereb Blood Flow Metab. 2013;34(3):376–379.
90. Picone P, Nuzzo D, Caruana L, et al. Mitochondrial dysfunction: different routes to Alzheimer’s disease therapy. Oxidative Medicine and Cellular Longevit. 2014;24:11.
91. Moreno–Ulloa A, Nogueira L, Rodriguez A, et al. Recovery of indicators of mitochondrial biogenesis, oxidative stress, and aging With (−)–epicatechin in senile mice. J Gerontol A Biol Sci Med Sci pii: glu. 2014;131.
92. Bause AS, Haigis MC. Sirt3 regulation of mitochondrial oxidative stress. Exp Gerontol. 2013;48(7):634–639.
93. Gan X, Huang S, Wu L, et al. Inhibition of ERK–DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer’s disease cybrid cell. Biochim Biophys Acta. 2014;1842(2):220–231.
94. Kaufman RJ, Malhotra JD. Calcium trafficking integrates endoplasmic reticulum function with mitochondrial bioenergetics. Biochim Biophys Acta. 2014;1843(10):2233–2239.
95. Dai SH, Chen T, Wang YH, et al. Sirt3 protects cortical neurons against oxidative stress via regulating mitochondrial Ca2+ and mitochondrial biogenesis. Int J Mol Sci. 2014;15(8):14591–14609.
96. Tseng AH, Shieh SS, Wang DL. Sirt3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med. 2013;63:222–234.
97. Zhao Y, Zhao B. Natural antioxidants in prevention and management of Alzheimer’s disease. Front Bio Sci (Elite Ed). 2012;4:794–808.
98. Marrache S, Dhar S. Engineering of blended nanoparticle platform for delivery of mitochondria–acting therapeutics. Proc Natl Acad U S A. 2012;109(40):16288–16293.
99. Cheng A, Hou Y, Mattson MP. Mitochondria and neuroplasticity. ASN Neuro. 2010;2(5):e00045.