Alzheimer’s disease (AD) is a major neurodegenerative disease affecting the elderly. Clinically, it is characterized by a progressive loss of memory and cognitive function. Neuropathologically, it is characterized by the presence of extracellular -amyloid (A ) deposited as neuritic plaques (NP) and neurofibrillary tangles (NFT) made of abnormal and hyperphosphorylated tau protein. These lesions are capable of generating the neuronal damage that leads to cell death and cognitive failure through the generation of reactive oxygen species (ROS). Evidence indicates the critical role of A metabolism in prompting the oxidative stress observed in AD patients. However, it has also been proposed that oxidative damage precedes the onset of clinical and pathological AD symptoms, including amyloid- deposition, neurofibrillary tangle formation, vascular malfunction, metabolic syndrome, and cognitive decline. This paper provides a brief description of the three main proteins associated with the development of the disease (A , tau, and ApoE) and describes their role in the generation of oxidative stress. Finally, we describe the mitochondrial alterations that are generated by A and examine the relationship of vascular damage which is a potential prognostic tool of metabolic syndrome. In addition, new therapeutic approaches targeting ROS sources and metabolic support were reported. 1. Introduction It has been speculated that the free radicals produced during oxidative stress are pathologically important in AD and other neurodegenerative diseases. Oxidative stress can be defined as an imbalance between ROS production and/or their elimination. That oxidative stress implicated in the etiology of AD is possibly due to changes in the redox status that occur in AD brains [1]. In recent years, it has been proposed that not only oxidative stress is a significant early event in the development of the disease, but also it plays an important role in modulating signaling pathways leading to cell death. Recent evidence has suggested that the presence of -amyloid is crucial in the development of the pathology. A results from the sequential proteolysis of the amyloid precursor protein (A PP) by -secretase (BACE1) and -secretase, a multiprotein complex. While, under physiological conditions, A appears to be unfolded, in pathological conditions, it is proposed that it increases the production of amyloid or its ability to aggregate [2, 3]. A toxicity is dependent on A ’s conformational state, peptide length, and concentration [4–8]. A deposition in the brain occurs not only in the
References
[1]
P. I. Moreira, A. Nunomura, M. Nakamura et al., “Nucleic acid oxidation in Alzheimer disease,” Free Radical Biology and Medicine, vol. 44, no. 8, pp. 1493–1505, 2008.
[2]
K. H. Ashe and K. R. Zahs, “Probing the biology of Alzheimer's disease in mice,” Neuron, vol. 66, no. 5, pp. 631–645, 2010.
[3]
K. R. Zahs and K. H. Ashe, “beta-Amyloid oligomers in aging and Alzheimer's disease,” Frontiers in Aging Neuroscience, vol. 5, p. 28, 2013.
[4]
M. Sakono and T. Zako, “Amyloid oligomers: formation and toxicity of Aβ oligomers,” The FEBS Journal, vol. 277, no. 6, pp. 1348–1358, 2010.
[5]
D. M. Walsh and D. J. Selkoe, “Oligomers in the brain: the emerging role of soluble protein aggregates in neurodegeneration,” Protein and Peptide Letters, vol. 11, no. 3, pp. 213–228, 2004.
[6]
D. Puzzo, L. Privitera, E. Leznik et al., “Picomolar amyloid-β positively modulates synaptic plasticity and memory in hippocampus,” Journal of Neuroscience, vol. 28, no. 53, pp. 14537–14545, 2008.
[7]
D. Puzzo, L. Privitera, and A. Palmeri, “Hormetic effect of amyloid-beta peptide in synaptic plasticity and memory,” Neurobiology of Aging, vol. 33, no. 7, pp. e15–e24, 2012.
[8]
R. M. Koffie, B. T. Hyman, and T. L. Spires-Jones, “Alzheimer's disease: synapses gone cold,” Molecular Neurodegeneration, vol. 6, no. 1, p. 63, 2011.
[9]
P. H. Reddy and M. F. Beal, “Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease,” Trends in Molecular Medicine, vol. 14, no. 2, pp. 45–53, 2008.
[10]
D. A. Butterfield and D. Boyd-Kimball, “The critical role of methionine 35 in Alzheimer's amyloid β-peptide (1-42)-induced oxidative stress and neurotoxicity,” Biochimica et Biophysica Acta, vol. 1703, no. 2, pp. 149–156, 2005.
[11]
D. A. Butterfield and A. I. Bush, “Alzheimer's amyloid β-peptide (1-42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide,” Neurobiology of Aging, vol. 25, no. 5, pp. 563–568, 2004.
[12]
D. A. Butterfield and J. Kanski, “Methionine residue 35 is critical for the oxidative stress and neurotoxic properties of Alzheimer's amyloid β-peptide 1-42,” Peptides, vol. 23, no. 7, pp. 1299–1309, 2002.
[13]
D. A. Butterfield, J. Drake, C. Pocernich, and A. Castegna, “Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptide,” Trends in Molecular Medicine, vol. 7, no. 12, pp. 548–554, 2001.
[14]
M. D. Weingarten, A. H. Lockwood, S. Y. Hwo, and M. W. Kirschner, “A protein factor essential for microtubule assembly,” Proceedings of the National Academy of Sciences of the United States of America, vol. 72, no. 5, pp. 1858–1862, 1975.
[15]
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.
[16]
R. Brandt, J. Léger, and G. Lee, “Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain,” Journal of Cell Biology, vol. 131, no. 5, pp. 1327–1340, 1995.
[17]
B. L. Goode, P. E. Denis, D. Panda et al., “Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly,” Molecular Biology of the Cell, vol. 8, no. 2, pp. 353–365, 1997.
[18]
M. D. Mukrasch, J. Biernat, M. von Bergen, C. Griesinger, E. Mandelkow, and M. Zweckstetter, “Sites of tau important for aggregation populate β-structure and bind to microtubules and polyanions,” Journal of Biological Chemistry, vol. 280, no. 26, pp. 24978–24986, 2005.
[19]
H. Braak and E. Braak, “Neuropathological stageing of Alzheimer-related changes,” Acta Neuropathologica, vol. 82, no. 4, pp. 239–259, 1991.
[20]
C. A. Lasagna-Reeves, D. L. Castillo-Carranza, U. Sengupta, et al., “Identification of oligomers at early stages of tau aggregation in Alzheimer's disease,” The FASEB Journal, vol. 26, no. 5, pp. 1946–1959, 2012.
[21]
K. R. Patterson, C. Remmers, Y. Fu et al., “Characterization of prefibrillar tau oligomers in vitro and in Alzheimer disease,” Journal of Biological Chemistry, vol. 286, no. 26, pp. 23063–23076, 2011.
[22]
S. I. Rapoport, “Coupled reductions in brain oxidative phosphorylation and synaptic function can be quantified and staged in the course of Alzheimer disease,” Neurotoxicity Research, vol. 5, no. 6, pp. 385–397, 2003.
[23]
C. A. Lasagna-Reeves, D. L. Castillo-Carranza, U. Sengupta, A. L. Clos, G. R. Jackson, and R. Kayed, “Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice,” Molecular Neurodegeneration, vol. 6, article 39, 2011.
[24]
L. Martin, X. Latypova, and F. Terro, “Post-translational modifications of tau protein: implications for Alzheimer's disease,” Neurochemistry International, vol. 58, no. 4, pp. 458–471, 2011.
[25]
R. A. Quintanilla, T. A. Matthews-Roberson, P. J. Dolan, and G. V. W. Johnsion, “Caspase-cleaved tau expression induces mitochondrial dysfunction in immortalized cortical neurons: implications for the pathogenesis of Alzheimer disease,” Journal of Biological Chemistry, vol. 284, no. 28, pp. 18754–18766, 2009.
[26]
C. A. Lasagna-Reeves, D. L. Castillo-Carranza, M. J. Guerrero-Mu？oz, G. R. Jackson, and R. Kayed, “Preparation and characterization of neurotoxic tau oligomers,” Biochemistry, vol. 49, no. 47, pp. 10039–10041, 2010.
[27]
A. Ferrari, F. Hoerndli, T. Baechi, R. M. Nitsch, and J. G？tz, “β-amyloid induces paired helical filament-like tau filaments in tissue culture,” Journal of Biological Chemistry, vol. 278, no. 41, pp. 40162–40168, 2003.
[28]
P. F. Good, D. P. Perl, L. M. Bierer, and J. Schmeidler, “Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: a laser microprobe (LAMMA) study,” Annals of Neurology, vol. 31, no. 3, pp. 286–292, 1992.
[29]
M. A. Smith, P. L. R. Harris, L. M. Sayre, and G. Perry, “Iron accumulation in Alzheimer disease is a source of redox-generated free radicals,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 18, pp. 9866–9868, 1997.
[30]
R. Resende, P. I. Moreira, T. Proen？a et al., “Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease,” Free Radical Biology and Medicine, vol. 44, no. 12, pp. 2051–2057, 2008.
[31]
B. Su, X. Wang, H.-G. Lee et al., “Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells,” Neuroscience Letters, vol. 468, no. 3, pp. 267–271, 2010.
[32]
Q. Liu, M. A. Smith, J. Avilá et al., “Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations,” Free Radical Biology and Medicine, vol. 38, no. 6, pp. 746–754, 2005.
[33]
Y.-J. Zhang, Y.-F. Xu, Y.-H. Liu et al., “Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms,” The FASEB Journal, vol. 20, no. 9, pp. 1431–1442, 2006.
[34]
R. W. Mahley, “Apolipoprotein E: cholesterol transport protein with expanding role in cell biology,” Science, vol. 240, no. 4852, pp. 622–630, 1988.
[35]
D. M. Hatters, C. A. Peters-Libeu, and K. H. Weisgraber, “Apolipoprotein E structure: insights into function,” Trends in Biochemical Sciences, vol. 31, no. 8, pp. 445–454, 2006.
[36]
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.
[37]
G. W. Munson, A. E. Roher, Y.-M. Kuo et al., “SDS-stable complex formation between native apolipoprotein E3 and β-amyloid peptides,” Biochemistry, vol. 39, no. 51, pp. 16119–16124, 2000.
[38]
D. M. Holtzman, “Role of apoE/Aβ interactions in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy,” Journal of Molecular Neuroscience, vol. 17, no. 2, pp. 147–155, 2001.
[39]
D. M. Holtzman, K. R. Bales, T. Tenkova et al., “Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 6, pp. 2892–2897, 2000.
[40]
S. Ye, Y. Huang, K. Müllendorff et al., “Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 51, pp. 18700–18705, 2005.
[41]
T. Hayek, J. Oiknine, J. G. Brook, and M. Aviram, “Increased plasma and lipoprotein lipid peroxidation in apo E-deficient mice,” Biochemical and Biophysical Research Communications, vol. 201, no. 3, pp. 1567–1574, 1994.
[42]
T. B. Shea, E. Rogers, D. Ashline, D. Ortiz, and M.-S. Sheu, “Apolipoprotein E deficiency promotes increased oxidative stress and compensatory increases in antioxidants in brain tissue,” Free Radical Biology and Medicine, vol. 33, no. 8, pp. 1115–1120, 2002.
[43]
M. Miyata and J. D. Smith, “Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and β-amyloid peptides,” Nature Genetics, vol. 14, no. 1, pp. 55–61, 1996.
[44]
H. Kharrazi, A. Vaisi-Raygani, Z. Rahimi, H. Tavilani, M. Aminian, and T. Pourmotabbed, “Association between enzymatic and non-enzymatic antioxidant defense mechanism with apolipoprotein E genotypes in Alzheimer disease,” Clinical Biochemistry, vol. 41, no. 12, pp. 932–936, 2008.
[45]
C. M. Lauderback, J. Kanski, J. M. Hackett, N. Maeda, M. S. Kindy, and D. A. Butterfield, “Apolipoprotein E modulates Alzheimer's Aβ(1-42)-induced oxidative damage to synaptosomes in an allele-specific manner,” Brain Research, vol. 924, no. 1, pp. 90–97, 2002.
[46]
C. Ramassamy, D. Averill, U. Beffert et al., “Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer's disease is related to the apolipoprotein E genotype,” Free Radical Biology and Medicine, vol. 27, no. 5-6, pp. 544–553, 1999.
[47]
F. Tchantchou, M. Graves, E. Rogers, D. Ortiz, and T. B. Shea, “N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency,” Journal of Alzheimer's Disease, vol. 7, no. 2, pp. 135–180, 2005.
[48]
P. Huebbe, L. Jofre-Monseny, C. Boesch-Saadatmandi, A.-M. Minihane, and G. Rimbach, “Effect of apoE genotype and vitamin E on biomarkers of oxidative stress in cultured neuronal cells and the brain of targeted replacement mice,” Journal of Physiology and Pharmacology, vol. 58, no. 4, pp. 683–698, 2007.
[49]
W. M. Saxton and P. J. Hollenbeck, “The axonal transport of mitochondria,” Journal of Cell Science, vol. 125, no. 9, pp. 2095–2104, 2012.
[50]
Z. Li, K.-I. Okamoto, Y. Hayashi, and M. Sheng, “The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses,” Cell, vol. 119, no. 6, pp. 873–887, 2004.
[51]
G. Bernard, N. Bellance, D. James et al., “Mitochondrial bioenergetics and structural network organization,” Journal of Cell Science, vol. 120, no. 5, pp. 838–848, 2007.
[52]
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.
[53]
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.
[54]
M. J. Calkins, M. Manczak, P. Mao, U. Shirendeb, and P. H. Reddy, “Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease,” Human Molecular Genetics, vol. 20, no. 23, pp. 4515–4529, 2011.
[55]
L. Tretter, I. Sipos, and V. Adam-Vizi, “Initiation of neuronal damage by complex I deficiency and oxidative stress in Parkinson's disease,” Neurochemical Research, vol. 29, no. 3, pp. 569–577, 2004.
[56]
M. T. Grijalba, A. E. Vercesi, and S. Schreier, “Ca2+-induced increased lipid packing and domain formation in submitochondrial particles. A possible early step in the mechanism of Ca2+- stimulated generation of reactive oxygen species by the respiratory chain,” Biochemistry, vol. 38, no. 40, pp. 13279–13287, 1999.
[57]
X. Wang, B. Su, H.-G. Lee et al., “Impaired balance of mitochondrial fission and fusion in Alzheimer's disease,” Journal of Neuroscience, vol. 29, no. 28, pp. 9090–9103, 2009.
[58]
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, pp. 2495–2509, 2011.
[59]
A. E. Mjaatvedt and M. T. T. Wong-Riley, “Relationship between synaptogenesis and cytochrome oxidase activity in Purkinje cells of the developing rat cerebellum,” Journal of Comparative Neurology, vol. 277, no. 2, pp. 155–182, 1988.
[60]
M. Jendrach, S. Mai, S. Pohl, M. V？th, and J. Bereiter-Hahn, “Short- and long-term alterations of mitochondrial morphology, dynamics and mtDNA after transient oxidative stress,” Mitochondrion, vol. 8, no. 4, pp. 293–304, 2008.
[61]
C. R. Jost, C. E. E. M. van der Zee, H. J. A. In 't Zandt et al., “Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility,” European Journal of Neuroscience, vol. 15, no. 10, pp. 1692–1706, 2002.
[62]
F. Streijger, F. Oerlemans, B. A. Ellenbroek, C. R. Jost, B. Wieringa, and C. E. E. M. van der Zee, “Structural and behavioural consequences of double deficiency for creatine kinases BCK and UbCKmit,” Behavioural Brain Research, vol. 157, no. 2, pp. 219–234, 2005.
[63]
T. S. Bürklen, U. Schlattner, R. Homayouni et al., “The creatine kinase/creatine connection to alzheimer's disease: CK-inactivation, APP-CK complexes and focal creatine deposits,” Journal of Biomedicine and Biotechnology, vol. 2006, Article ID 35936, 11 pages, 2006.
[64]
C. Iadecola, “Neurovascular regulation in the normal brain and in Alzheimer's disease,” Nature Reviews Neuroscience, vol. 5, no. 5, pp. 347–360, 2004.
[65]
L. Park, J. Anrather, P. Zhou et al., “NADPH oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid β peptide,” Journal of Neuroscience, vol. 25, no. 7, pp. 1769–1777, 2005.
[66]
L. Park, P. Zhou, R. Pitstick et al., “Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 4, pp. 1347–1352, 2008.
[67]
J. Leszek, M. Sochocka, and K. Gasiorowski, “Vascular factors and epigenetic modifications in the pathogenesis of Alzheimer's disease,” Journal of the Neurological Sciences, vol. 323, no. 1-2, pp. 25–32, 2012.
[68]
T. F. Luscher and G. Noll, “The pathogenesis of cardiovascular disease: role of the endothelium as a target and mediator,” Atherosclerosis, 118, pp. S81–S90, 1995.
[69]
H. A. Kim, A. A. Miller, G. R. Drummond, et al., “Vascular cognitive impairment and Alzheimer's disease: role of cerebral hypoperfusion and oxidative stress,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 385, no. 10, pp. 953–959, 2012.
[70]
M. Sochocka, E. S. Koutsouraki, K. Gasiorowski, and J. Leszek, “Vascular oxidative stress and mitochondrial failure in the pathobiology of Alzheimer's disease: new approach to therapy,” CNS and Neurological Disorders, vol. 12, no. 6, pp. 870–881, 2013.
[71]
G. Aliev, H. H. Palacios, B. Walrafen, A. E. Lipsitt, M. E. Obrenovich, and L. Morales, “Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease,” International Journal of Biochemistry and Cell Biology, vol. 41, no. 10, pp. 1989–2004, 2009.
[72]
R. O. Akinyemi, E. B. Mukaetova-Ladinska, J. Attems, M. Ihara, and R. N. Kalaria, “Vascular risk factors and neurodegeneration in ageing related dementias: Alzheimer's disease and vascular dementia,” Current Alzheimer Research, vol. 10, no. 6, pp. 642–653, 2013.
[73]
L. Nelson, N. Tabet, C. Richardson, and P. Gard, “Antihypertensives, angiotensin, glucose and Alzheimer's disease,” Expert Review of Neurotherapeutics, vol. 13, no. 5, pp. 477–482, 2013.
[74]
R. E. Schmieder, K. F. Hilgers, M. P. Schlaich, and B. M. Schmidt, “Renin-angiotensin system and cardiovascular risk,” The Lancet, vol. 369, no. 9568, pp. 1208–1219, 2007.
[75]
J. M. Saavedra, “Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders,” Clinical Science, vol. 123, no. 10, pp. 567–590, 2012.
[76]
M. Mogi, J. Iwanami, and M. Horiuchi, “Roles of brain angiotensin II in cognitive function and dementia,” International Journal of Hypertension, vol. 2012, Article ID 169649, 7 pages, 2012.
[77]
H. Girouard, L. Park, J. Anrather, P. Zhou, and C. Iadecola, “Angiotensin II attenuates endothelium-dependent responses in the cerebral microcirculation through nox-2-derived radicals,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 4, pp. 826–832, 2006.
[78]
K. Kazama, J. Anrather, P. Zhou et al., “Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals,” Circulation Research, vol. 95, no. 10, pp. 1019–1026, 2004.
[79]
C. Capone, G. Faraco, L. Park, X. Cao, R. L. Davisson, and C. Iadecola, “The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension,” The American Journal of Physiology, vol. 300, no. 1, pp. H397–H407, 2011.
[80]
N. C. Li, A. Lee, R. A. Whitmer et al., “Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis,” BMJ, vol. 340, Article ID b5465, 2010.
[81]
N. M. Davies, P. G. Kehoe, Y. Ben-Shlomo, and R. M. Martin, “Associations of anti-hypertensive treatments with Alzheimer's disease, vascular dementia, and other dementias,” Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 699–708, 2011.
[82]
S. Takeda, N. Sato, D. Takeuchi et al., “Angiotensin receptor blocker prevented β-amyloid-induced cognitive impairment associated with recovery of neurovascular coupling,” Hypertension, vol. 54, no. 6, pp. 1345–1352, 2009.
[83]
M. Mogi and M. Horiuchi, “Effects of angiotensin II receptor blockers on dementia,” Hypertension Research, vol. 32, no. 9, pp. 738–740, 2009.
[84]
J. C. de La Torre, “Alzheimer's disease is a vasocognopathy: a new term to describe its nature,” Neurological Research, vol. 26, no. 5, pp. 517–524, 2004.
[85]
B. V. Zlokovic, “Neurovascular mechanisms of Alzheimer's neurodegeneration,” Trends in Neurosciences, vol. 28, no. 4, pp. 202–208, 2005.
[86]
Y. F. Dong, K. Kataoka, Y. Tokutomi et al., “Perindopril, a centrally active angiotensin-converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer's disease,” The FASEB Journal, vol. 25, no. 9, pp. 2911–2920, 2011.
[87]
H. J. Milionis, M. Florentin, and S. Giannopoulos, “Metabolic syndrome and alzheimer's disease: a link to a vascular hypothesis?” CNS Spectrums, vol. 13, no. 7, pp. 606–613, 2008.
[88]
J. Drake, C. D. Link, and D. A. Butterfield, “Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid β-peptide (1-42) in a transgenic Caenorhabditis elegans model,” Neurobiology of Aging, vol. 24, no. 3, pp. 415–420, 2003.
[89]
W. Q. Qiu, M. Mwamburi, L. M. Besser, et al., “Angiotensin converting enzyme inhibitors and the reduced risk of Alzheimer's disease in the absence of apolipoprotein E4 allele,” Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 421–428, 2013.
[90]
A. Csiszar, Z. Tucsek, P. Toth, et al., “Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in beta-amyloid generation and Alzheimer's disease,” The American Journal of Physiology. Heart and Circulatory Physiology, vol. 305, no. 8, pp. H1120–H1130, 2013.
[91]
M. A. LaFontaine, M. P. Mattson, and D. A. Butterfield, “Oxidative stress in synaptosomal proteins from mutant presenilin-1 knock-in mice: implications for familial Alzheimer's disease,” Neurochemical Research, vol. 27, no. 5, pp. 417–421, 2002.
[92]
D. Bosco, A. Fava, M. Plastino, T. Montalcini, and A. Pujia, “Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis,” Journal of Cellular and Molecular Medicine, vol. 15, no. 9, pp. 1807–1821, 2011.
[93]
R. P. Friedland, T. F. Budinger, and E. Ganz, “Regional cerebral metabolic alterations in dementia of the Alzheimer type: positron emission tomography with [18F]fluorodeoxyglucose,” Journal of Computer Assisted Tomography, vol. 7, no. 4, pp. 590–598, 1983.
[94]
B. Erd？s, J. A. Snipes, A. W. Miller, and D. W. Busija, “Cerebrovascular dysfunction in zucker obese rats is mediated by oxidative stress and protein kinase C,” Diabetes, vol. 53, no. 5, pp. 1352–1359, 2004.
[95]
G. M. Pasinetti and J. A. Eberstein, “Metabolic syndrome and the role of dietary lifestyles in Alzheimer's disease,” Journal of Neurochemistry, vol. 106, no. 4, pp. 1503–1514, 2008.
[96]
S. Craft, “The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged,” Archives of Neurology, vol. 66, no. 3, pp. 300–305, 2009.
