Alzheimer’s disease (AD) is the most common cause of dementia in elderly adults. It is estimated that 10% of the world’s population aged more than 60–65 years could currently be affected by AD, and that in the next 20 years, there could be more than 30 million people affected by this pathology. One of the great challenges in this regard is that AD is not just a scientific problem; it is associated with major psychosocial and ethical dilemmas and has a negative impact on national economies. The neurodegenerative process that occurs in AD involves a specific nervous cell dysfunction, which leads to neuronal death. Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer’s disease and the association between some of these mutations with both oxidative damage and the development of the pathology. 1. Introduction Brain requires a high consumption of oxygen to generate adenosine triphosphate (ATP). It is known that oxygen metabolism in the mitochondria, endoplasmic reticulum (ER), and peroxisomes generates oxidant agents known as free radicals [1, 2], small molecules with unpaired electron that includes the oxygen reactive species (ROS) like hydroxyl radical ( ), superoxide radical ( ), the reactive nitrogen species (RNS), and nitric oxide ( ). These molecules show high reactivity with macromolecules [3] and have an important biological function as signaling molecules [4]. However the interaction of these agents and nonradical oxidants with membrane lipids, proteins, and DNA also could be conducted to cellular senescence. This oxidative damage is catalyzed by the presence of trace elements Fe, Cu or both [5]. As part of evolution, organisms have developed enzymatic and nonenzymatic antioxidants mechanism to counteract oxidative damage, which act removing free radicals, scavenging ROS/RNS or their precursors and binding trace elements [1]. The antioxidant enzymes are superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx). The nonenzymatic antioxidants group is composed of the natural molecules glutathione (GSH) and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), and compounds like ascorbic and lipoic acid, polyphenols and carotenoids dietary derived [6]. However, an imbalance of oxidants and antioxidants agents could generate oxidative
References
[1]
Y. Gilgun-Sherki, E. Melamed, and D. Offen, “Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier,” Neuropharmacology, vol. 40, no. 8, pp. 959–975, 2001.
[2]
M. Velayutham, C. Hemann, and J. L. Zweier, “Removal of H2O2 and generation of superoxide radical: role of cytochrome c and NADH,” Free Radical Biology and Medicine, vol. 51, no. 1, pp. 160–170, 2011.
[3]
B. Uttara, A. V. Singh, P. Zamboni, and R. T. Mahajan, “Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options,” Current Neuropharmacology, vol. 7, no. 1, pp. 65–74, 2009.
[4]
S. Nemoto, K. Takeda, Z.-X. Yu, V. J. Ferrans, and T. Finkel, “Role for mitochondrial oxidants as regulators of cellular metabolism,” Molecular and Cellular Biology, vol. 20, no. 19, pp. 7311–7318, 2000.
[5]
R. A. Floyd and J. M. Carney, “Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress,” Annals of Neurology, vol. 32, pp. S22–S27, 1992.
[6]
E. Shohami, E. Beit-Yannai, M. Horowitz, and R. Kohen, “Oxidative stress in closed-head injury: brain antioxidant capacity as an indicator of functional outcome,” Journal of Cerebral Blood Flow and Metabolism, vol. 17, no. 10, pp. 1007–1019, 1997.
[7]
D. P. Jones, “Radical-free biology of oxidative stress,” American Journal of Physiology, vol. 295, no. 4, pp. C849–C868, 2008.
[8]
D. Nguyen, M. V. Alavi, K.-Y. Kim et al., “A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics,” Cell Death and Disease, vol. 2, no. 12, p. e240, 2011.
[9]
A. Federico, E. Cardaioli, P. Da Pozzo, P. Formichi, G. Gallus, and E. Radi, “Mitochondria, oxidative stress and neurodegeneration,” Journal of the Neurological Sciences, vol. 322, no. 1-2, pp. 254–262, 2012.
[10]
G. McKhann, D. Drachman, and M. Folstein, “Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease,” Neurology, vol. 34, no. 7, pp. 939–944, 1984.
[11]
E. B. Mukaetova-Ladinska, C. R. Harrington, M. Roth, and C. M. Wischik, “Biochemical and anatomical redistribution of tau protein in Alzheimer's disease,” American Journal of Pathology, vol. 143, no. 2, pp. 565–578, 1993.
[12]
K. Fukuchi, M. Hart, and L. Li, “Alzheimer's disease and heparan sulfate proteoglycan,” Frontiers in Bioscience, vol. 3, pp. 327–337, 1998.
[13]
A. L. Bergem, K. Engedal, and E. Kringlen, “The role of heredity in late-onset Alzheimer disease and vascular dementia: a twin study,” Archives of General Psychiatry, vol. 54, no. 3, pp. 264–270, 1997.
[14]
M. Gatz, C. A. Reynolds, L. Fratiglioni et al., “Role of genes and environments for explaining Alzheimer disease,” Archives of General Psychiatry, vol. 63, no. 2, pp. 168–174, 2006.
[15]
I. R？ih？, J. Kaprio, M. Koskenvuo, T. Rajala, and L. Sourander, “Alzheimer's disease in Finnish twins,” The Lancet, vol. 347, no. 9001, pp. 573–578, 1996.
[16]
S. Aleshkov, C. R. Abraham, and V. I. Zannis, “Interaction of nascent apoe2, apoe3, and apoe4 isoforms expressed in mammalian cells with amyloid peptide β (1-40). Relevance to Alzheimer's disease,” Biochemistry, vol. 36, no. 34, pp. 10571–10580, 1997.
[17]
E. H. Corder, A. M. Saunders, W. J. Strittmatter et al., “Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families,” Science, vol. 261, no. 5123, pp. 921–923, 1993.
[18]
A. M. Saunders, W. J. Strittmatter, D. Schmechel et al., “Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer's disease,” Neurology, vol. 43, no. 8, pp. 1467–1472, 1993.
[19]
W. J. Strittmatter and A. D. Roses, “Apolipoprotein E and Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 11, pp. 4725–4727, 1995.
[20]
N. Ertekin-Taner, “Genetics of Alzheimer's disease: a centennial review,” Neurologic Clinics, vol. 25, no. 3, pp. 611–667, 2007.
[21]
J. Kim, J. M. Basak, and D. M. Holtzman, “The Role of Apolipoprotein E in Alzheimer's Disease,” Neuron, vol. 63, no. 3, pp. 287–303, 2009.
[22]
G. W. Roberts, M. Nash, P. G. Ince, M. C. Royston, and S. M. Gentleman, “On the origin of Alzheimer's disease: a hypothesis,” NeuroReport, vol. 4, no. 1, pp. 7–9, 1993.
[23]
R. D. Terry, E. Masliah, D. P. Salmon et al., “Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment,” Annals of Neurology, vol. 30, no. 4, pp. 572–580, 1991.
[24]
B. E. C. Tomlinson, “Ageing and the dementias,” in Greenfield's Neuropathologyed, J. C. Hume Adams and L. W. Duchen, Eds., Edward Arnold, London, UK, 1984.
[25]
G. Blessed, B. E. Tomlinson, and M. Roth, “The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects,” British Journal of Psychiatry, vol. 114, no. 512, pp. 797–811, 1968.
[26]
H. Braak and E. Braak, “Staging of Alzheimer-related cortical destruction,” International Psychogeriatrics, vol. 9, supplement 1, pp. 257–272, 1997.
[27]
A. Andreadis, W. M. Brown, and K. S. Kosik, “Structure and novel exons of the human τ gene,” Biochemistry, vol. 31, no. 43, pp. 10626–10633, 1992.
[28]
D. J. Ennulat, R. K. H. Liem, G. A. Hashim, and M. L. Shelanski, “Two separate 18-amino acid domains of tau promote the polymerization of tubulin,” Journal of Biological Chemistry, vol. 264, no. 10, pp. 5327–5330, 1989.
[29]
M. Goedert, M. G. Spillantini, R. Jakes, D. Rutherford, and R. A. Crowther, “Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease,” Neuron, vol. 3, no. 4, pp. 519–526, 1989.
[30]
M. Goedert, C. M. Wischik, R. A. Crowther, J. E. Walker, and A. Klug, “Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 11, pp. 4051–4055, 1988.
[31]
D. W. Cleveland, S. Y. Hwo, and M. W. Kirschner, “Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly,” Journal of Molecular Biology, vol. 116, no. 2, pp. 227–247, 1977.
[32]
O. Schweers, E. Sch？nbrunn-Hanebeck, A. Marx, and E. Mandelkow, “Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for β-structure,” Journal of Biological Chemistry, vol. 269, no. 39, pp. 24290–24297, 1994.
[33]
M. Goedert and A. Klug, “Tau protein and the paired helical filament of Alzheimer's disease,” Brain Research Bulletin, vol. 50, no. 5-6, pp. 469–470, 1999.
[34]
C. Ballatore, V. M.-Y. Lee, and J. Q. Trojanowski, “Tau-mediated neurodegeneration in Alzheimer's disease and related disorders,” Nature Reviews Neuroscience, vol. 8, no. 9, pp. 663–672, 2007.
[35]
F. Chen, D. David, A. Ferrari, and J. G？tz, “Posttranslational modifications of tau—role in human tauopathies and modeling in transgenic animals,” Current Drug Targets, vol. 5, no. 6, pp. 503–515, 2004.
[36]
F. Hernández and J. Avila, “Tauopathies,” Cellular and Molecular Life Sciences, vol. 64, no. 17, pp. 2219–2233, 2007.
[37]
M. Hutton, “Molecular genetics of chromosome 17 tauopathies,” Annals of the New York Academy of Sciences, vol. 920, pp. 63–73, 2000.
[38]
M. Hutton, C. L. Lendon, P. Rizzu et al., “Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17,” Nature, vol. 393, no. 6686, pp. 702–705, 1998.
[39]
P. Poorkaj, T. Bird, E. Wijsman, et al., “Tau is a candidate gene for chromosome 17 frontotemporal dementia,” Annals of Neurology, vol. 43, no. 6, pp. 815–825, 1998.
[40]
M. G. Spillantini, T. D. Bird, and B. Ghetti, “Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies,” Brain Pathology, vol. 8, no. 2, pp. 387–402, 1998.
[41]
L. L. Iversen, R. J. Mortishire-Smith, S. J. Pollack, and M. S. Shearman, “The toxicity in vitro of β-amyloid protein,” Biochemical Journal, vol. 311, no. 1, pp. 1–16, 1995.
[42]
G. G. Glenner, C. W. Wong, V. Quaranta, and E. D. Eanes, “The amyloid deposits in Alzheimer's disease: their nature and pathogenesis,” Applied Pathology, vol. 2, no. 6, pp. 357–369, 1984.
[43]
D. J. Selkoe, “Alzheimer's disease: a central role for amyloid,” Journal of Neuropathology and Experimental Neurology, vol. 53, no. 5, pp. 438–447, 1994.
[44]
J. Kang, H.-G. Lemaire, and A. Unterbeck, “The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor,” Nature, vol. 325, no. 6106, pp. 733–736, 1987.
[45]
A. Schmitz, R. Tikkanen, G. Kirfel, and V. Herzog, “The biological role of the Alzheimer amyloid precursor protein in epithelial cells,” Histochemistry and Cell Biology, vol. 117, no. 2, pp. 171–180, 2002.
[46]
D. Schubert, L. Jin, T. Saitoh, and G. Cole, “The regulation of amyloid β protein precursor secretion and its modulatory role in cell adhesion,” Neuron, vol. 3, no. 6, pp. 689–694, 1989.
[47]
R. A. Crowther and C. M. Wischik, “Image reconstruction of the Alzheimer paired helical filament,” The EMBO Journal B, vol. 4, no. 13, pp. 3661–3665, 1985.
[48]
P. R. Turner, K. O'Connor, W. P. Tate, and W. C. Abraham, “Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory,” Progress in Neurobiology, vol. 70, no. 1, pp. 1–32, 2003.
[49]
C. Priller, T. Bauer, G. Mitteregger, B. Krebs, H. A. Kretzschmar, and J. Herms, “Synapse formation and function is modulated by the amyloid precursor protein,” The Journal of Neuroscience, vol. 26, no. 27, pp. 7212–7221, 2006.
[50]
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.
[51]
T. Li, G. Ma, H. Cai, D. L. Price, and P. C. Wong, “Nicastrin is required for assembly of presenilin/γ-secretase complexes to mediate notch signaling and for processing and trafficking of β-amyloid precursor protein in mammals,” Journal of Neuroscience, vol. 23, no. 8, pp. 3272–3277, 2003.
[52]
Y. Li, M. Lai, M. Xu et al., “Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 11, pp. 6138–6143, 2000.
[53]
G. Yu, M. Nishimura, S. Arawaka et al., “Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing,” Nature, vol. 407, no. 6800, pp. 48–54, 2000.
[54]
M. Sakono and T. Zako, “Amyloid oligomers: formation and toxicity of Aβ oligomers,” FEBS Journal, vol. 277, no. 6, pp. 1348–1358, 2010.
[55]
L. Kulic, J. McAfoose, T. Welt, et al., “Early accumulation of intracellular fibrillar oligomers and late congophilic amyloid angiopathy in mice expressing the Osaka intra-Abeta APP mutation,” Translational Psychiatry, vol. 2, p. e183, 2012.
[56]
I. Benilova, E. Karran, and B. De Strooper, “The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes,” Nature Neuroscience, vol. 15, no. 3, pp. 349–357, 2012.
[57]
M. A. Deibel, W. D. Ehmann, and W. R. Markesbery, “Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress,” Journal of the Neurological Sciences, vol. 143, no. 1-2, pp. 137–142, 1996.
[58]
C. Opazo, X. Huang, R. A. Cherny et al., “Metalloenzyme-like activity of Alzheimer's disease β-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2,” Journal of Biological Chemistry, vol. 277, no. 43, pp. 40302–40308, 2002.
[59]
D. Jiang, X. Li, R. Williams et al., “Ternary complexes of iron, amyloid-β, and nitrilotriacetic acid: binding affinities, redox properties, and relevance to iron-induced oxidative stress in Alzheimer's disease,” Biochemistry, vol. 48, no. 33, pp. 7939–7947, 2009.
[60]
M. P. Cuajungco, L. E. Goldstein, A. Nunomura et al., “Evidence that the β-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of Aβ by zinc,” Journal of Biological Chemistry, vol. 275, no. 26, pp. 19439–19442, 2000.
[61]
S. M. Yatin, S. Varadarajan, C. D. Link, and D. A. Butterfield, “In vitro and in vivo oxidative stress associated with Alzheimer's amyloid β-peptide (1–42),” Neurobiology of Aging, vol. 20, no. 3, pp. 325–342, 1999.
[62]
D. A. Butterfield, V. Galvan, M. B. Lange et al., “In vivo oxidative stress in brain of Alzheimer disease transgenic mice: requirement for methionine 35 in amyloid β-peptide of APP,” Free Radical Biology and Medicine, vol. 48, no. 1, pp. 136–144, 2010.
[63]
K. J. Barnham, G. D. Ciccotosto, A. K. Tickler et al., “Neurotoxic, redox-competent Alzheimer's β-amyloid is released from lipid membrane by methionine oxidation,” Journal of Biological Chemistry, vol. 278, no. 44, pp. 42959–42965, 2003.
[64]
J. Moskovitz, P. Maiti, D. H. J. Lopes et al., “Induction of methionine-sulfoxide reductases protects neurons from amyloid β-protein insults in vitro and in vivo,” Biochemistry, vol. 50, no. 49, pp. 10687–10697, 2011.
[65]
M. A. Meraz-Rios, D. Toral-Rios, D. Franco-Bocanegra, J. Villeda-Hernandez, and V. Campos-Pena, “Inflammatory process in Alzheimer's disease,” Frontiers in Integrative Neuroscience, vol. 7, p. 59, 2013.
[66]
F. G. De Felice, P. T. Velasco, M. P. Lambert et al., “Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine,” Journal of Biological Chemistry, vol. 282, no. 15, pp. 11590–11601, 2007.
[67]
P. B. Shelat, M. Chalimoniuk, J. Wang et al., “Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cytosolic phospholipase A2 in cortical neurons,” Journal of Neurochemistry, vol. 106, no. 1, pp. 45–55, 2008.
[68]
M. Y. Cha, S. Han, S. M. Son et al., “Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death,” PLoS ONE, vol. 7, no. 4, Article ID e34929, 2012.
[69]
A. Y. Abramov, L. Canevari, and M. R. Duchen, “β-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase,” Journal of Neuroscience, vol. 24, no. 2, pp. 565–575, 2004.
[70]
M. Buttini, E. Masliah, R. Barbour et al., “β-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease,” Journal of Neuroscience, vol. 25, no. 40, pp. 9096–9101, 2005.
[71]
D. R. Borchelt, G. Thinakaran, C. B. Eckman et al., “Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo,” Neuron, vol. 17, no. 5, pp. 1005–1013, 1996.
[72]
M. C. Chartier-Harlin, F. Crawford, K. Hamandi et al., “Screening for the β-amyloid precursor protein mutation (APP717: Val → Ile) in extended pedigrees with early onset Alzheimer's disease,” Neuroscience Letters, vol. 129, no. 1, pp. 134–135, 1991.
[73]
K. Duff, C. Eckman, C. Zehr et al., “Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1,” Nature, vol. 383, no. 6602, pp. 710–713, 1996.
[74]
A. Goate, M.-C. Chartier-Harlin, M. Mullan et al., “Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease,” Nature, vol. 349, no. 6311, pp. 704–706, 1991.
[75]
D. M. Kovacs, H. J. Fausett, K. J. Page et al., “Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells,” Nature Medicine, vol. 2, no. 2, pp. 224–229, 1996.
[76]
E. Levy-Lahad, E. M. Wijsman, E. Nemens et al., “A familial Alzheimer's disease locus on chromosome I,” Science, vol. 269, no. 5226, pp. 970–973, 1995.
[77]
J. Murrell, M. Farlow, B. Ghetti, and M. D. Benson, “A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease,” Science, vol. 254, no. 5028, pp. 97–99, 1991.
[78]
D. Scheuner, C. Eckman, M. Jensen et al., “Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease,” Nature Medicine, vol. 2, no. 8, pp. 864–870, 1996.
[79]
S. S. Sisodia, S. H. Kim, and G. Thinakaran, “Function and dysfunction of the presenilins,” American Journal of Human Genetics, vol. 65, no. 1, pp. 7–12, 1999.
[80]
E. Levy, M. D. Carman, I. J. Fernandez-Madrid et al., “Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type,” Science, vol. 248, no. 4959, pp. 1124–1126, 1990.
[81]
M. Mullan, F. Crawford, K. Axelman et al., “A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of β-amyloid,” Nature Genetics, vol. 1, no. 5, pp. 345–347, 1992.
[82]
C. B. Eckman, N. D. Mehta, R. Crook et al., “A new pathogenic mutation in the APP gene (1716V) increases the relative proportion of Aβ42(43),” Human Molecular Genetics, vol. 6, no. 12, pp. 2087–2089, 1997.
[83]
T. J. Grabowski, H. S. Cho, J. P. G. Vonsattel, G. William Rebeck, and S. M. Greenberg, “Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy,” Annals of Neurology, vol. 49, no. 6, pp. 697–705, 2001.
[84]
C. Nilsberth, A. Westlind-Danielsson, C. B. Eckman et al., “The “Arctic” APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation,” Nature Neuroscience, vol. 4, no. 9, pp. 887–893, 2001.
[85]
J. Nunan and D. H. Small, “Regulation of APP cleavage by α-, β- and γ-secretases,” FEBS Letters, vol. 483, no. 1, pp. 6–10, 2000.
[86]
R. G. Perez, S. L. Squazzo, and E. H. Koo, “Enhanced release of amyloid β-protein from codon 670/671 “Swedish” mutant β-amyloid precursor protein occurs in both secretory and endocytic pathways,” Journal of Biological Chemistry, vol. 271, no. 15, pp. 9100–9107, 1996.
[87]
H. Du, L. Guo, S. Yan, A. A. Sosunov, G. M. McKhann, and S. S. Yan, “Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 43, pp. 18670–18675, 2010.
[88]
A. Bobba, G. Amadoro, D. Valenti, V. Corsetti, R. Lassandro, and A. Atlante, “Mitochondrial respiratory chain complexes I and IV are impaired by beta-amyloid via direct interaction and through complex I-dependent ROS production, respectively,” Mitochondrion, vol. 13, no. 4, pp. 298–311, 2013.
[89]
R. Ren, Y. Zhang, B. Lee, Y. Wu, and B. Li, “Effect of β-amyloid (25–35) on mitochondrial function and expression of mitochondrial permeability transition pore proteins in rat hippocampal neurons,” Journal of Cellular Biochemistry, vol. 112, no. 5, pp. 1450–1457, 2011.
[90]
M. Manczak, M. J. Calkins, and P. H. Reddy, “Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage,” Human Molecular Genetics, vol. 20, no. 13, Article ID ddr139, pp. 2495–2509, 2011.
[91]
T. Jungas, I. Motta, F. Duffieux, P. Fanen, V. Stoven, and D. M. Ojcius, “Glutathione levels and BAX activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant cystic fibrosis transmembrane conductance regulator,” Journal of Biological Chemistry, vol. 277, no. 31, pp. 27912–27918, 2002.
[92]
S. Hauptmann, I. Scherping, S. Dr？se et al., “Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice,” Neurobiology of Aging, vol. 30, no. 10, pp. 1574–1586, 2009.
[93]
D. Praticò, K. Uryu, S. Leight, J. Q. Trojanoswki, and V. M.-Y. Lee, “Increased lipid peroxidation precedes amyloid plaque formation in an animal model of alzheimer amyloidosis,” Journal of Neuroscience, vol. 21, no. 12, pp. 4183–4187, 2001.
[94]
D. A. Butterfield, M. L. Bader Lange, and R. Sultana, “Involvements of the lipid peroxidation product, HNE, in the pathogenesis and progression of Alzheimer's disease,” Biochimica et Biophysica Acta, vol. 1801, no. 8, pp. 924–929, 2010.
[95]
J. Apelt, M. Bigl, P. Wunderlich, and R. Schliebs, “Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology,” International Journal of Developmental Neuroscience, vol. 22, no. 7, pp. 475–484, 2004.
[96]
M. Manczak, T. S. Anekonda, E. Henson, B. S. Park, J. Quinn, and P. H. Reddy, “Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression,” Human Molecular Genetics, vol. 15, no. 9, pp. 1437–1449, 2006.
[97]
V. Blanchard, S. Moussaoui, C. Czech et al., “Time sequence of maturation of dystrophic neurites associated with Aβ deposits in APP/PS1 transgenic mice,” Experimental Neurology, vol. 184, no. 1, pp. 247–263, 2003.
[98]
K. Schuessel, S. Sch？fer, T. A. Bayer et al., “Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice,” Neurobiology of Disease, vol. 18, no. 1, pp. 89–99, 2005.
[99]
R. Sherrington, S. Froelich, S. Sorbi et al., “Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant,” Human Molecular Genetics, vol. 5, no. 7, pp. 985–988, 1996.
[100]
J. H. Chyung, D. M. Raper, and D. J. Selkoe, “γ-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage,” Journal of Biological Chemistry, vol. 280, no. 6, pp. 4383–4392, 2005.
[101]
M. Réchards, W. Xia, V. M. J. Oorschot, D. J. Selkoe, and J. Klumperman, “Presenilin-1 exist in both pre- and post-golgi compartments and recycles via COPI-coated membranes,” Traffic, vol. 4, no. 8, pp. 553–565, 2003.
[102]
K. S. Vetrivel, H. Cheng, W. Lin et al., “Association of γ-secretase with lipid rafts in post-golgi and endosome membranes,” Journal of Biological Chemistry, vol. 279, no. 43, pp. 44945–44954, 2004.
[103]
J. O. Ebinu and B. A. Yankner, “A RIP tide in neuronal signal transduction,” Neuron, vol. 34, no. 4, pp. 499–502, 2002.
[104]
L. Kulic, J. Walter, G. Multhaup et al., “Separation of presenilin function in amyloid β-peptide generation and endoproteolysis of Notch,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 11, pp. 5913–5918, 2000.
[105]
P. Marambaud, J. Shioi, G. Serban et al., “A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions,” EMBO Journal, vol. 21, no. 8, pp. 1948–1956, 2002.
[106]
R. Vassar and M. Citron, “Aβ-generating enzymes: recent advances in β- and γ-secretase research,” Neuron, vol. 27, no. 3, pp. 419–422, 2000.
[107]
J. T. Yu, J. Song, T. Ma et al., “Genetic association of PICALM polymorphisms with Alzheimer's disease in Han Chinese,” Journal of the Neurological Sciences, vol. 300, no. 1-2, pp. 78–80, 2011.
[108]
S. Naruse, G. Thinakaran, J. Luo et al., “Effects of PS1 deficiency on membrane protein trafficking in neurons,” Neuron, vol. 21, no. 5, pp. 1213–1221, 1998.
[109]
K. G. Pratt, E. C. Zimmerman, D. G. Cook, and J. M. Sullivan, “Presenilin 1 regulates homeostatic synaptic scaling through Akt signaling,” Nature Neuroscience, vol. 14, no. 9, pp. 1112–1114, 2011.
[110]
C. A. Saura, E. Servián-Morilla, and F. G. Scholl, “Presenilin/γ-secretase regulates neurexin processing at synapses,” PLoS ONE, vol. 6, no. 4, Article ID e19430, 2011.
[111]
T. Shimizu, T. Toda, Y. Noda, G. Ito, and M. Maeda, “Presenilin-2 mutation causes early amyloid accumulation and memory impairment in a transgenic mouse model of Alzheimer's disease,” Journal of Biomedicine and Biotechnology, vol. 2011, Article ID 617974, 12 pages, 2011.
[112]
C. Supnet and I. Bezprozvanny, “Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis,” Cell Calcium, vol. 50, no. 3, pp. 303–309, 2011.
[113]
H. Zhang, S. Sun, A. Herreman, B. De Strooper, and I. Bezprozvanny, “Role of presenilins in neuronal calcium homeostasis,” Journal of Neuroscience, vol. 30, no. 25, pp. 8566–8580, 2010.
[114]
C. Zhang, B. Wu, V. Beglopoulos et al., “Presenilins are essential for regulating neurotransmitter release,” Nature, vol. 460, no. 7255, pp. 632–636, 2009.
[115]
A. Louvi, S. S. Sisodia, and E. A. Grove, “Presenilin 1 in migration and morphogenesis in the central nervous system,” Development, vol. 131, no. 13, pp. 3093–3105, 2004.
[116]
J. Busciglio, H. Hartmann, A. Lorenzo et al., “Neuronal localization of presenilin-1 and association with amyloid plaques and neurofibrillary tangles in Alzheimer's disease,” Journal of Neuroscience, vol. 17, no. 13, pp. 5101–5107, 1997.
[117]
H. Jacobsen, D. Reinhardt, M. Brockhaus et al., “The influence of endoproteolytic processing of familial Alzheimer's disease presenilin 2 on Aβ42 amyloid peptide formation,” Journal of Biological Chemistry, vol. 274, no. 49, pp. 35233–35239, 1999.
[118]
E. Storey and R. Cappai, “The amyloid precursor protein of Alzheimer's disease and the Aβ peptide,” Neuropathology and Applied Neurobiology, vol. 25, no. 2, pp. 81–97, 1999.
[119]
M. S. Wolfe, J. De Los Angeles, D. D. Miller, W. Xia, and D. J. Selkoe, “Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease,” Biochemistry, vol. 38, no. 35, pp. 11223–11230, 1999.
[120]
M. S. Wolfe, W. Xia, B. L. Ostaszewski, T. S. Diehl, W. T. Kimberly, and D. J. Selkoe, “Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity,” Nature, vol. 398, no. 6727, pp. 513–517, 1999.
[121]
T. Wisniewski, W. K. Dowjat, J. D. Buxbaum et al., “A novel polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years,” NeuroReport, vol. 9, no. 2, pp. 217–221, 1998.
[122]
D. Campion, A. Brice, C. Dumanchin et al., “A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years,” NeuroReport, vol. 7, no. 10, pp. 1582–1584, 1996.
[123]
J. Shen, R. T. Bronson, D. F. Chen, W. Xia, D. J. Selkoe, and S. Tonegawa, “Skeletal and CNS defects in Presenilin-1-deficient mice,” Cell, vol. 89, no. 4, pp. 629–639, 1997.
[124]
M. Citron, D. Westaway, W. Xia et al., “Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice,” Nature Medicine, vol. 3, no. 1, pp. 67–72, 1997.
[125]
C. Casas, N. Sergeant, J. Itier et al., “Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Aβ42 accumulation in a novel Alzheimer transgenic model,” American Journal of Pathology, vol. 165, no. 4, pp. 1289–1300, 2004.
[126]
D. Z. Christensen, S. L. Kraus, A. Flohr, M. Cotel, O. Wirths, and T. A. Bayer, “Transient intraneuronal Aβ rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice,” Acta Neuropathologica, vol. 116, no. 6, pp. 647–655, 2008.
[127]
H. Breyhan, O. Wirths, K. Duan, A. Marcello, J. Rettig, and T. A. Bayer, “APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy,” Acta Neuropathologica, vol. 117, no. 6, pp. 677–685, 2009.
[128]
G. Pigino, G. Morfini, A. Pelsman, M. P. Mattson, S. T. Brady, and J. Busciglio, “Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport,” Journal of Neuroscience, vol. 23, no. 11, pp. 4499–4508, 2003.
[129]
G. Prihar, R. A. Fuldner, J. Perez-Tur et al., “Structure and alternative splicing of the presenilin-2 gene,” NeuroReport, vol. 7, no. 10, pp. 1680–1684, 1996.
[130]
A. Herreman, D. Hartmann, W. Annaert et al., “Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 21, pp. 11872–11877, 1999.
[131]
D. Y. Yuk, Y. K. Lee, S. Y. Nam et al., “Reduced anxiety in the mice expressing mutant (N141I) presenilin 2,” Journal of Neuroscience Research, vol. 87, no. 2, pp. 522–531, 2009.
[132]
M. Bentahir, O. Nyabi, J. Verhamme et al., “Presenilin clinical mutations can affect γ-secretase activity by different mechanisms,” Journal of Neurochemistry, vol. 96, no. 3, pp. 732–742, 2006.
[133]
S. G. Lindquist, L. Hasholt, J. M. C. Bahl et al., “A novel presenilin 2 mutation (V393M) in early-onset dementia with profound language impairment,” European Journal of Neurology, vol. 15, no. 10, pp. 1135–1139, 2008.
[134]
K. Schuessel, C. Frey, C. Jourdan et al., “Aging sensitizes toward ROS formation and lipid peroxidation in PS1M146L transgenic mice,” Free Radical Biology and Medicine, vol. 40, no. 5, pp. 850–862, 2006.
[135]
J. G. Begley, W. Duan, S. Chan, K. Duff, and M. P. Mattson, “Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice,” Journal of Neurochemistry, vol. 72, no. 3, pp. 1030–1039, 1999.
[136]
S. Sung, Y. Yao, K. Uryu et al., “Early vitamin E supplementation in young but not aged mice reduces Abeta levels and amyloid deposition in a transgenic model of Alzheimer's disease,” The FASEB Journal, vol. 18, no. 2, pp. 323–325, 2004.
[137]
G. M. Cole and S. A. Frautschy, “Docosahexaenoic acid protects from amyloid and dendritic pathology in an Alzheimer's disease mouse model,” Nutrition and Health, vol. 18, no. 3, pp. 249–259, 2006.
[138]
S. L. Siedlak, G. Casadesus, K. M. Webber et al., “Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer's disease,” Free Radical Research, vol. 43, no. 2, pp. 156–164, 2009.
[139]
N. Dragicevic, N. Copes, G. O'Neal-Moffitt et al., “Melatonin treatment restores mitochondrial function in Alzheimer's mice: a mitochondrial protective role of melatonin membrane receptor signaling,” Journal of Pineal Research, vol. 51, no. 1, pp. 75–86, 2011.
[140]
M. J. Mcmanus, M. P. Murphy, and J. L. Franklin, “The mitochondria-targeted antioxidant mitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease,” Journal of Neuroscience, vol. 31, no. 44, pp. 15703–15715, 2011.
[141]
M. L. Peacock, D. L. Murman, A. A. F. Sima, J. T. Warren Jr., A. D. Roses, and J. K. Fink, “Novel amyloid precursor protein gene mutation (codon 665(Asp)) in a patient with late-onset Alzheimer's disease,” Annals of Neurology, vol. 35, no. 4, pp. 432–438, 1994.
[142]
J. C. Janssen, J. A. Beck, T. A. Campbell et al., “Early onset familial Alzheimer's disease: mutation frequency in 31 families,” Neurology, vol. 60, no. 2, pp. 235–239, 2003.
[143]
Y. Wakutani, K. Watanabe, Y. Adachi et al., “Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer's disease,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 75, no. 7, pp. 1039–1042, 2004.
[144]
T. Tomiyama, T. Nagata, H. Shimada et al., “A new amyloid β variant favoring oligomerization in Alzheimer's-type dementia,” Annals of Neurology, vol. 63, no. 3, pp. 377–387, 2008.
[145]
D. A. Carter, E. Desmarais, M. Bellis et al., “More missense in amyloid gene,” Nature Genetics, vol. 2, no. 4, pp. 255–256, 1992.
[146]
P. Pasalar, H. Najmabadi, A. R. Noorian et al., “An Iranian family with Alzheimer's disease caused by a novel APP mutation (THr714ALa),” Neurology, vol. 58, no. 10, pp. 1574–1575, 2002.
[147]
S. Kumar-Singh, C. De Jonghe, M. Cruts et al., “Nonfibrillar diffuse amyloid deposition due to a γ42-secretase site mutation points to an essential role for N-truncated Aβ42 in Alzheimer's disease,” Human Molecular Genetics, vol. 9, no. 18, pp. 2589–2598, 2000.
[148]
C. De Jonghe, C. Esselens, S. Kumar-Singh et al., “Pathogenic APP mutations near the γ-secretase cleavage site differentially affect Aβ secretion and APP C-terminal fragment stability,” Human Molecular Genetics, vol. 10, no. 16, pp. 1665–1671, 2001.
[149]
M. Cruts, B. Dermaut, R. Rademakers, M. Van Den Broeck, F. St？gbauer, and C. Van Broeckhoven, “Novel APP mutation V715A associated with presenile Alzheimer's disease in a German family,” Journal of Neurology, vol. 250, no. 11, pp. 1374–1375, 2003.
[150]
K. Ancolio, C. Dumanchin, H. Barelli et al., “Unusual phenotypic alteration of β amyloid precursor protein (βAPP) maturation by a new Val-715 → Met βAPP-770 mutation responsible for probable early-onset Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 7, pp. 4119–4124, 1999.
[151]
L. Terreni, S. Fogliarino, Franceschi, and G. Forloni, “Novel pathogenic mutation in an Italian patient with familial Alzheimer's disease detected in APP gene,” Neurobiology of Aging, vol. 23, supplement 1, p. S319, 2002.
[152]
R. Ghidoni, V. Albertini, R. Squitti et al., “Novel T719P AβPP mutation unbalances the relative proportion of amyloid-β peptides,” Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 295–303, 2009.
[153]
J. B. Kwok, Q. X. Li, M. Hallupp, et al., “Novel Leu723Pro amyloid precursor protein mutation increases amyloid β42(43) peptide levels and induces apoptosis,” Annals of Neurology, vol. 47, no. 2, pp. 249–253, 2000.
