Table of Contents Author Guidelines Submit a Manuscript
Oxidative Medicine and Cellular Longevity
Volume 2015, Article ID 803942, 8 pages
http://dx.doi.org/10.1155/2015/803942
Review Article

Alzheimer’s Pathogenesis and Its Link to the Mitochondrion

Department of Experimental and Clinical Medicine, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, Italy

Received 30 December 2014; Revised 16 March 2015; Accepted 2 April 2015

Academic Editor: Trevor A. Mori

Copyright © 2015 C. Simoncini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. Alzheimer, Über einen Eigenartigen Schweren Erkrankungsprozess der Hirnrinde, Neurologisches Centralblatt, Tübingen, Germany, 1906.
  2. A. Alzheimer, “Über eine eigenartige Erkrankung der Hirnrinde,” Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin, vol. 64, pp. 146–148, 1907. View at Google Scholar
  3. G. Perusini, “Über klinisch und histologisch eigenartige psychische Erkrankungen des späteren Lebensalters,” Histologische und Histopathologlsche Arbeiten, vol. 3, no. 2, pp. 197–351, 1910. View at Google Scholar
  4. G. B. Irvine, O. M. El-Agnaf, G. M. Shankar, and D. M. Walsh, “Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases,” Molecular Medicine, vol. 14, no. 7-8, pp. 451–464, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. M. Mancuso, D. Orsucci, A. LoGerfo, V. Calsolaro, and G. Siciliano, “Clinical features and pathogenesis of Alzheimer's disease: involvement of mitochondria and mitochondrial DNA,” Advances in Experimental Medicine and Biology, vol. 685, pp. 34–44, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. R. Katzman, “Alzheimer's disease,” The New England Journal of Medicine, vol. 314, no. 15, pp. 964–973, 1986. View at Publisher · View at Google Scholar · View at Scopus
  7. M. A. Smith, “Alzheimer disease,” International Review of Neurobiology, vol. 42, pp. 1–54, 1998. View at Publisher · View at Google Scholar · View at Scopus
  8. C. L. Masters, G. Simms, N. A. Weinman, G. Multhaup, B. L. McDonald, and K. Beyreuther, “Amyloid plaque core protein in Alzheimer disease and Down syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 12, pp. 4245–4249, 1985. View at Publisher · View at Google Scholar · View at Scopus
  9. I. Grundke-Iqbal, K. Iqbal, M. Quinlan, Y. C. Tung, M. S. Zaidi, and H. M. Wisniewski, “Microtubule associated protein tau. A component of Alzheimer paired helical filaments,” The Journal of Biological Chemistry, vol. 261, no. 13, pp. 6084–6089, 1986. View at Google Scholar · View at Scopus
  10. W. E. Klunk, H. Engler, A. Nordberg et al., “Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B,” Annals of Neurology, vol. 55, no. 3, pp. 306–319, 2004. View at Publisher · View at Google Scholar · View at Scopus
  11. M. T. Fodero-Tavoletti, N. Okamura, S. Furumoto et al., “18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease,” Brain, vol. 134, no. 4, pp. 1089–1100, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. R. C. Petersen, R. Doody, A. Kurz et al., “Current concepts in mild cognitive impairment,” Archives of Neurology, vol. 58, no. 12, pp. 1985–1992, 2001. View at Publisher · View at Google Scholar · View at Scopus
  13. D. S. Knopman, B. F. Boeve, and R. C. Petersen, “Essentials of the proper diagnoses of mild cognitive impairment, dementia, and major subtypes of dementia,” Mayo Clinic Proceedings, vol. 78, no. 10, pp. 1290–1308, 2003. View at Publisher · View at Google Scholar · View at Scopus
  14. R. C. Petersen, “Mild cognitive impairment as a diagnostic entity,” Journal of Internal Medicine, vol. 256, no. 3, pp. 183–194, 2004. View at Publisher · View at Google Scholar · View at Scopus
  15. B. Nacmias, I. Piaceri, S. Bagnoli, A. Tedde, S. Piacentini, and S. Sorbi, “Genetics of Alzheimer's disease and frontotemporal dementia,” Current Molecular Medicine, vol. 14, no. 8, pp. 993–1000, 2014. View at Google Scholar
  16. J. Hardy and D. J. Selkoe, “The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics,” Science, vol. 297, no. 5580, pp. 353–356, 2002. View at Publisher · View at Google Scholar · View at Scopus
  17. R. Vassar, B. D. Bennett, S. Babu-Khan et al., “β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE,” Science, vol. 286, no. 5440, pp. 735–741, 1999. View at Publisher · View at Google Scholar · View at Scopus
  18. W. T. Kimberly, M. J. LaVoie, B. L. Ostaszewski, W. Ye, M. S. Wolfe, and D. J. Selkoe, “γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 11, pp. 6382–6387, 2003. View at Publisher · View at Google Scholar · View at Scopus
  19. D. M. Walsh, B. P. Tseng, R. E. Rydel, M. B. Podlisny, and D. J. Selkoe, “The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain,” Biochemistry, vol. 39, no. 35, pp. 10831–10839, 2000. View at Publisher · View at Google Scholar · View at Scopus
  20. R. H. Takahashi, C. G. Almeida, P. F. Kearney et al., “Oligomerization of Alzheimers beta-amyloid within processes and synapses of cultured neurons and brain,” The Journal of Neuroscience, vol. 24, no. 14, pp. 3592–3599, 2004. View at Publisher · View at Google Scholar · View at Scopus
  21. G. K. Gouras, J. Tsai, J. Naslund et al., “Intraneuronal Aβ42 accumulation in human brain,” The American Journal of Pathology, vol. 156, no. 1, pp. 15–20, 2000. View at Publisher · View at Google Scholar · View at Scopus
  22. O. Wirths, G. Multhaup, and T. A. Bayer, “A modified β-amyloid hypothesis: intraneuronal accumulation of the β-amyloid peptide—the first step of a fatal cascade,” Journal of Neurochemistry, vol. 91, no. 3, pp. 513–520, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. C. S. Casley, L. Canevari, J. M. Land, J. B. Clark, and M. A. Sharpe, “Beta amyloid inhibts integrated mitochondrial respiration and key enzyme activities,” Journal of Neurochemistry, vol. 80, no. 1, pp. 91–100, 2002. View at Publisher · View at Google Scholar · View at Scopus
  24. S. Raha and B. H. Robinson, “Mitochondria, oxygen free radicals, and apoptosis,” American Journal of Medical Genetics, vol. 106, no. 1, pp. 62–70, 2001. View at Publisher · View at Google Scholar · View at Scopus
  25. D. J. Bonda, X. Wang, G. Perry et al., “Oxidative stress in Alzheimer disease: a possibility for prevention,” Neuropharmacology, vol. 59, no. 4-5, pp. 290–294, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. E. C. Ienco, C. Simoncini, D. Orsucci et al., “May ‘mitochondrial eve’ and mitochondrial haplogroups play a role in neurodegeneration and alzheimer's disease?” International Journal of Alzheimer's Disease, vol. 2011, Article ID 709061, 11 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. N. P. Azari, K. D. Pettigrew, M. B. Schapiro et al., “Early detection of Alzheimer's disease: a statistical approach using positron emission tomographic data,” Journal of Cerebral Blood Flow & Metabolism, vol. 13, no. 3, pp. 438–447, 1993. View at Publisher · View at Google Scholar · View at Scopus
  28. J. P. Blass, R. K.-F. Sheu, and G. E. Gibson, “Inherent abnormalities in energy metabolism in Alzheimer disease: interaction with cerebrovascular compromise,” Annals of the New York Academy of Sciences, vol. 903, pp. 204–221, 2000. View at Publisher · View at Google Scholar · View at Scopus
  29. D. C. Wallace, “Mitochondrial diseases in man and mouse,” Science, vol. 283, no. 5407, pp. 1482–1488, 1999. View at Publisher · View at Google Scholar · View at Scopus
  30. G. E. Gibson, V. Haroutunian, H. Zhang et al., “Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype,” Annals of Neurology, vol. 48, no. 3, pp. 297–303, 2000. View at Publisher · View at Google Scholar · View at Scopus
  31. P. Bubber, V. Haroutunian, G. Fisch, J. P. Blass, and G. E. Gibson, “Mitochondrial abnormalities in Alzheimer brain: mechanistic implications,” Annals of Neurology, vol. 57, no. 5, pp. 695–703, 2005. View at Publisher · View at Google Scholar · View at Scopus
  32. W. S. Liang, E. M. Reiman, J. Valla et al., “Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 11, pp. 4441–4446, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. K. Henze and W. Martin, “Evolutionary biology: essence of mitochondria,” Nature, vol. 426, no. 6963, pp. 127–128, 2003. View at Google Scholar
  34. S. Di Mauro and E. A. Schon, “Mitochondrial respiratory-chain diseases,” The New England Journal of Medicine, vol. 348, no. 26, pp. 2656–2668, 2003. View at Publisher · View at Google Scholar · View at Scopus
  35. H. Noji and M. Yoshida, “The rotary machine in the cell, ATP synthase,” The Journal of Biological Chemistry, vol. 276, no. 3, pp. 1665–1668, 2001. View at Publisher · View at Google Scholar · View at Scopus
  36. M. F. Beal, “Mitochondria take center stage in aging and neurodegeneration,” Annals of Neurology, vol. 58, no. 4, pp. 495–505, 2005. View at Publisher · View at Google Scholar · View at Scopus
  37. J. B. Schulz, J. Lindenau, J. Seyfried, and J. Dichgans, “Glutathione, oxidative stress and neurodegeneration,” European Journal of Biochemistry, vol. 267, no. 16, pp. 4904–4911, 2000. View at Publisher · View at Google Scholar · View at Scopus
  38. E. Mariani, M. C. Polidori, A. Cherubini, and P. Mecocci, “Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview,” Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, vol. 827, no. 1, pp. 65–75, 2005. View at Publisher · View at Google Scholar · View at Scopus
  39. W. J. H. Koopman, F. Distelmaier, J. A. M. Smeitink, and P. H. G. M. Willems, “OXPHOS mutations and neurodegeneration,” The EMBO Journal, vol. 32, no. 1, pp. 9–29, 2013. View at Publisher · View at Google Scholar · View at Scopus
  40. J. Avila, “Common mechanisms in neurodegeneration,” Nature Medicine, vol. 16, no. 12, article 1372, 2010. View at Publisher · View at Google Scholar · View at Scopus
  41. M. Filosto, M. Scarpelli, M. S. Cotelli et al., “The role of mitochondria in neurodegenerative diseases,” Journal of Neurology, vol. 258, no. 10, pp. 1763–1774, 2011. View at Publisher · View at Google Scholar · View at Scopus
  42. X. Zhu, G. Perry, M. A. Smitha, and X. Wang, “Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 33, supplement 1, pp. S253–S262, 2013. View at Publisher · View at Google Scholar · View at Scopus
  43. P. I. Moreira, C. Carvalho, X. Zhu, M. A. Smith, and G. Perry, “Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology,” Biochimica et Biophysica Acta, vol. 1802, no. 1, pp. 2–10, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. D. B. Zorov, M. Juhaszova, and S. J. Sollott, “Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release,” Physiological Reviews, vol. 94, no. 3, pp. 909–950, 2014. View at Publisher · View at Google Scholar
  45. M. Mancuso, F. Coppedè, L. Murri, and G. Siciliano, “Mitochondrial cascade hypothesis of Alzheimer's disease: myth or reality?” Antioxidants and Redox Signaling, vol. 10, pp. 1631–1646, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. R. X. Santos, S. C. Correia, X. Wang et al., “A synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 20, no. 2, pp. S401–S412, 2010. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Sano, C. Ernesto, R. G. Thomas et al., “A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study,” The New England Journal of Medicine, vol. 336, no. 17, pp. 1216–1222, 1997. View at Publisher · View at Google Scholar · View at Scopus
  48. R. C. Petersen, R. G. Thomas, M. Grundman et al., “Vitamin E and donepezil for the treatment of mild cognitive impairment,” The New England Journal of Medicine, vol. 352, no. 23, pp. 2379–2388, 2005. View at Publisher · View at Google Scholar · View at Scopus
  49. M. Dumont, K. Kipiani, F. Yu et al., “Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 211–223, 2011. View at Publisher · View at Google Scholar · View at Scopus
  50. R. H. Swerdlow, J. K. Parks, D. S. Cassarino et al., “Cybrids in Alzheimer's disease: a cellular model of the disease?” Neurology, vol. 49, no. 4, pp. 918–925, 1997. View at Publisher · View at Google Scholar · View at Scopus
  51. G. N. Bijur, R. E. Davis, and R. S. Jope, “Rapid activation of heat shock factor-1 DNA binding by H2O2 and modulation by glutathione in human neuroblastoma and Alzheimer's disease cybrid cells,” Molecular Brain Research, vol. 71, no. 1, pp. 69–77, 1999. View at Publisher · View at Google Scholar · View at Scopus
  52. S. M. Cardoso, I. Santana, R. H. Swerdlow, and C. R. Oliveira, “Mitochondria dysfunction of Alzheimer's disease cybrids enhances Aβ toxicity,” Journal of Neurochemistry, vol. 89, no. 6, pp. 1417–1426, 2004. View at Publisher · View at Google Scholar · View at Scopus
  53. P. de Sarno, G. N. Bijur, R. Lu, R. E. Davis, and R. S. Jope, “Alterations in muscarinic receptor-coupled phosphoinositide hydrolysis and AP-1 activation in Alzheimer's disease cybrid cells,” Neurobiology of Aging, vol. 21, no. 1, pp. 31–38, 2000. View at Publisher · View at Google Scholar · View at Scopus
  54. I. G. Onyango, J.-Y. Ahn, J. B. Tuttle, J. P. Bennett Jr., and R. H. Swerdlow, “Nerve growth factor attenuates oxidant-induced beta-amyloid neurotoxicity in sporadic Alzheimer's disease cybrids,” Journal of Neurochemistry, vol. 114, no. 6, pp. 1605–1618, 2010. View at Publisher · View at Google Scholar · View at Scopus
  55. H. Zhang, Y. Liu, M. Lao, Z. Ma, and X. Yi, “Puerarin protects Alzheimer's disease neuronal cybrids from oxidant-stress induced apoptosis by inhibiting pro-death signaling pathways,” Experimental Gerontology, vol. 46, no. 1, pp. 30–37, 2011. View at Publisher · View at Google Scholar · View at Scopus
  56. L. Chen, S.-E. Yoo, R. Na, Y. Liu, and Q. Ran, “Cognitive impairment and increased Aβ levels induced by paraquat exposure are attenuated by enhanced removal of mitochondrial H2O2,” Neurobiology of Aging, vol. 33, no. 2, pp. 432.e15–432.e26, 2012. View at Publisher · View at Google Scholar · View at Scopus
  57. J. L. Elson, C. Herrnstadt, G. Preston et al., “Does the mitochondrial genome play a role in the etiology of Alzheimer's disease?” Human Genetics, vol. 119, no. 3, pp. 241–254, 2006. View at Publisher · View at Google Scholar · View at Scopus
  58. P. Chagnon, M. Gee, M. Filion, Y. Robitaille, M. Belouchi, and D. Gauvreau, “Phylogenetic analysis of the mitochondrial genome indicates significant differences between patients with Alzheimer disease and controls in a French-Canadian founder population,” American Journal of Medical Genetics, vol. 85, no. 1, pp. 20–30, 1999. View at Publisher · View at Google Scholar · View at Scopus
  59. G. Carrieri, M. Bonafè, M. de Luca et al., “Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease,” Human Genetics, vol. 108, no. 3, pp. 194–198, 2001. View at Publisher · View at Google Scholar · View at Scopus
  60. J. M. van der Walt, Y. A. Dementieva, E. R. Martin et al., “Analysis of European mitochondrial haplogroups with Alzheimer disease risk,” Neuroscience Letters, vol. 365, no. 1, pp. 28–32, 2004. View at Publisher · View at Google Scholar · View at Scopus
  61. P. F. Chinnery, G. A. Taylor, N. Howell et al., “Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies,” Neurology, vol. 55, no. 2, pp. 302–304, 2000. View at Publisher · View at Google Scholar · View at Scopus
  62. M. Mancuso, M. Nardini, D. Micheli et al., “Lack of association between mtDNA haplogroups and Alzheimer's disease in Tuscany,” Neurological Sciences, vol. 28, no. 3, pp. 142–147, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Mancuso, M. Filosto, D. Orsucci, and G. Siciliano, “Mitochondrial DNA sequence variation and neurodegeneration,” Human Genomics, vol. 3, no. 1, pp. 71–78, 2008. View at Publisher · View at Google Scholar · View at Scopus
  64. E. Levy and M. D. Carman, “Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage Dutch type,” Science, vol. 248, no. 4959, pp. 1124–1126, 1990. View at Publisher · View at Google Scholar · View at Scopus
  65. F. Li, N. Y. Calingasan, F. Yu et al., “Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice,” Journal of Neurochemistry, vol. 89, no. 5, pp. 1308–1312, 2004. View at Publisher · View at Google Scholar · View at Scopus
  66. L. Esposito, J. Raber, L. Kekonius et al., “Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice,” The Journal of Neuroscience, vol. 26, no. 19, pp. 5167–5179, 2006. View at Publisher · View at Google Scholar · View at Scopus
  67. H. K. Anandatheerthavarada, G. Biswas, M.-A. Robin, and N. G. Avadhani, “Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells,” Journal of Cell Biology, vol. 161, no. 1, pp. 41–54, 2003. View at Publisher · View at Google Scholar · View at Scopus
  68. K. Xiong, H. Cai, X.-G. Luo, R. G. Struble, R. W. Clough, and X.-X. Yan, “Mitochondrial respiratory inhibition and oxidative stress elevate β-secretase (BACE1) proteins and activity in vivo in the rat retina,” Experimental Brain Research, vol. 181, no. 3, pp. 435–446, 2007. View at Publisher · View at Google Scholar · View at Scopus
  69. L. Wahlster, M. Arimon, N. Nasser-Ghodsi et al., “Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer's disease,” Acta Neuropathologica, vol. 125, no. 2, pp. 187–199, 2013. View at Publisher · View at Google Scholar · View at Scopus
  70. E. Borger, L. Aitken, K. E. A. Muirhead et al., “Mitochondrial β-amyloid in Alzheimer's disease,” Biochemical Society Transactions, vol. 39, no. 4, pp. 868–873, 2011. View at Publisher · View at Google Scholar · View at Scopus
  71. E. Borger, L. Aitken, H. Du, W. Zhang, F. J. Gunn-Moore, and S. S. D. Yan, “Is amyloid binding alcohol dehydrogenase a drug target for treating Alzheimer's disease?” Current Alzheimer Research, vol. 10, no. 1, pp. 21–29, 2013. View at Google Scholar · View at Scopus
  72. C. A. Hansson Petersen, N. Alikhani, H. Behbahani et al., “The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 35, pp. 13145–13150, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. W. Neupert and J. M. Herrmann, “Translocation of proteins into mitochondria,” Annual Review of Biochemistry, vol. 76, pp. 723–749, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. P. Rehling, N. Pfanner, and C. Meisinger, “Insertion of hydrophobic membrane proteins into the inner mitochondrial membrane—a guided tour,” Journal of Molecular Biology, vol. 326, no. 3, pp. 639–657, 2003. View at Publisher · View at Google Scholar · View at Scopus
  75. D. Lindholm, O. Eriksson, and L. Korhonen, “Mitochondrial proteins in neuronal degeneration,” Biochemical and Biophysical Research Communications, vol. 321, no. 4, pp. 753–758, 2004. View at Publisher · View at Google Scholar · View at Scopus
  76. C. S. Casley, L. Canevari, J. M. Land, J. B. Clark, and M. A. Sharpe, “Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities,” Journal of Neurochemistry, vol. 80, no. 1, pp. 91–100, 2002. View at Publisher · View at Google Scholar · View at Scopus
  77. S. A. Detmer and D. C. Chan, “Functions and dysfunctions of mitochondrial dynamics,” Nature Reviews Molecular Cell Biology, vol. 8, no. 11, pp. 870–879, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. A. E. Frazier, C. Kiu, D. Stojanovski, N. J. Hoogenraad, and M. T. Ryan, “Mitochondrial morphology and distribution in mammalian cells,” Biological Chemistry, vol. 387, no. 12, pp. 1551–1558, 2006. View at Publisher · View at Google Scholar · View at Scopus
  79. L. M. Ittner, Y. D. Ke, F. Delerue et al., “Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models,” Cell, vol. 142, no. 3, pp. 387–397, 2010. View at Publisher · View at Google Scholar · View at Scopus
  80. E. D. Roberson, B. Halabisky, J. W. Yoo et al., “Amyloid-β/fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of alzheimer's disease,” The Journal of Neuroscience, vol. 31, no. 2, pp. 700–711, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. A. L. Guillozet, S. Weintraub, D. C. Mash, and M. Marsel Mesulam, “Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment,” Archives of Neurology, vol. 60, no. 5, pp. 729–736, 2003. View at Publisher · View at Google Scholar · View at Scopus
  82. C. S. Arnold, G. V. W. Johnson, R. N. Cole, D. L.-Y. Dong, M. Lee, and G. W. Hart, “The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine,” The Journal of Biological Chemistry, vol. 271, no. 46, pp. 28741–28744, 1996. View at Publisher · View at Google Scholar · View at Scopus
  83. T. J. Cohen, J. L. Guo, D. E. Hurtado et al., “The acetylation of tau inhibits its function and promotes pathological tau aggregation,” Nature Communications, vol. 2, no. 1, article 252, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. S. Melov, P. A. Adlard, K. Morten et al., “Mitochondrial oxidative stress causes hyperphosphorylation of tau,” PLoS ONE, vol. 2, no. 6, article e536, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. I. Santa-María, F. Hernández, C. Pérez Martín, J. Avila, and F. J. Moreno, “Quinones facilitate the self-assembly of the phosphorylated tubulin binding region of tau into fibrillar polymers,” Biochemistry, vol. 43, no. 10, pp. 2888–2897, 2004. View at Publisher · View at Google Scholar · View at Scopus
  86. K. J. Kopeikina, G. A. Carlson, R. Pitstick et al., “Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer's disease brain,” The American Journal of Pathology, vol. 179, no. 4, pp. 2071–2082, 2011. View at Publisher · View at Google Scholar · View at Scopus
  87. G. L. Mancardi, F. Perdelli, C. Rivano, A. Leonardi, and O. Bugiani, “Thickening of the basement membrane of cortical capillaries in Alzheimer's disease,” Acta Neuropathologica, vol. 49, no. 1, pp. 79–83, 1980. View at Publisher · View at Google Scholar · View at Scopus
  88. G. Perry, M. A. Smith, C. E. McCann, S. L. Siedlak, P. K. Jones, and R. P. Friedland, “Cerebrovascular muscle atrophy is a feature of Alzheimer's disease,” Brain Research, vol. 791, no. 1-2, pp. 63–66, 1998. View at Publisher · View at Google Scholar · View at Scopus
  89. A. E. Roher, C. Esh, A. Rahman, T. A. Kokjohn, and T. G. Beach, “Atherosclerosis of cerebral arteries in Alzheimer disease,” Stroke, vol. 35, no. 11, pp. 2623–2627, 2004. View at Publisher · View at Google Scholar · View at Scopus
  90. D. Orsucci, M. Mancuso, E. Caldarazzo Ienco, C. Simoncini, G. Siciliano, and U. Bonuccelli, “Vascular factors and mitochondrial dysfunction: a central role in the pathogenesis of Alzheimer's disease,” Current Neurovascular Research, vol. 10, no. 1, pp. 76–80, 2013. View at Publisher · View at Google Scholar · View at Scopus
  91. A. Ruitenberg, T. den Heijer, S. L. M. Bakker et al., “Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study,” Annals of Neurology, vol. 57, no. 6, pp. 789–794, 2005. View at Publisher · View at Google Scholar · View at Scopus
  92. X. Zhu, M. A. Smith, K. Honda et al., “Vascular oxidative stress in Alzheimer disease,” Journal of the Neurological Sciences, vol. 257, no. 1-2, pp. 240–246, 2007. View at Publisher · View at Google Scholar · View at Scopus
  93. A. Nunomura, G. Perry, M. A. Pappolla et al., “RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease,” The Journal of Neuroscience, vol. 19, no. 6, pp. 1959–1964, 1999. View at Google Scholar · View at Scopus
  94. A. Nunomura, S. Chiba, C. F. Lippa et al., “Neuronal RNA oxidation is a prominent feature of familial Alzheimer's disease,” Neurobiology of Disease, vol. 17, no. 1, pp. 108–113, 2004. View at Publisher · View at Google Scholar · View at Scopus
  95. A. Aliyev, S. G. Chen, D. Seyidova et al., “Mitochondria DNA deletions in atherosclerotic hypoperfused brain microvessels as a primary target for the development of Alzheimer's disease,” Journal of the Neurological Sciences, vol. 229-230, pp. 285–292, 2005. View at Publisher · View at Google Scholar · View at Scopus
  96. G. Hudson, R. Sims, D. Harold et al., “No consistent evidence for association between mtDNA variants and Alzheimer disease,” Neurology, vol. 78, no. 14, pp. 1038–1042, 2012. View at Publisher · View at Google Scholar · View at Scopus
  97. L. Rajendran and W. Annaert, “Membrane trafficking pathways in Alzheimer's disease,” Traffic, vol. 13, no. 6, pp. 759–770, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. C. Haass, C. Kaether, G. Thinakaran, and S. Sisodia, “Trafficking and proteolytic processing of APP,” Cold Spring Harbor Perspectives in Medicine, vol. 2, no. 5, Article ID a006270, 2012. View at Publisher · View at Google Scholar · View at Scopus