Abstract
Cognitive impairment and psychiatric disturbances in Alzheimer’s disease (AD) result from the dysfunction and degeneration of synapses, and consequent death of neurons, in the limbic system and associated regions of the cerebral cortex. A major molecular alteration in AD is increased amyloidogenic processing of the amyloid precursor protein (APP) resulting in increased production and accumulation of amyloid b-peptide (Ab) in the brain. Ab may promote synaptic dysfunction and can render neurons vulnerable to excitotoxicity and apoptosis by a mechanism involving oxidative stress and disruption of cellular calcium homeostasis. Some cases of inherited AD are caused by mutations in presenilins (PS)1 and PS2, which perturb cellular calcium homeostasis. Abnormalities in astrocytes, oligodendrocytes, and microglia have also been documented in studies of experimental models of AD, suggesting contributions of these alterations to neuronal dysfunction and cell death.
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References
DeKosky ST, Orgogozo JM. Alzheimer disease: diagnosis, costs, and dimensions of treatment. Alzheimer Dis Assoc Disord 2001;15:S3–7.
Engelborghs S, De Deyn PP. The neurochemistry of Alzheimer’s disease. Acta Neurol Belg 1997; 97:67–84
Buhot MC, Martin S, Segu L. Role of serotonin in memory impairment. Ann Med 2000;32: 210–221.
Braak H, Braak E, Yilmazer D, de Vos RA, Jansen EN, Bohl J. Pattern of brain destruction in Parkinson’s and Alzheimer’s diseases. J. Neural. Transm. 1996;103:455–490.
Kromer Vogt LJ, Hyman BT, Van Hoesen GW, Damasio AR. Pathological alterations in the amygdala in Alzheimer’s disease. Neuroscience 1990;37:377–385.
Callen DJ, Black SE, Gao F, Caldwell CB, Szalai JP. Beyond the hippocampus: MRI volumetry confirms widespread limbic atrophy in AD. Neurology 2001;57:1669–1674.
Yankner BA. Mechanisms of neuronal degeneration in Alzheimer’s disease. Neuron 1996;16: 921–932.
Mattson MP. Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 1997;77:1081–1132.
Mark RJ, Hensley K, Butterfield DA, Mattson MP. Amyloid beta-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal calcium homeostasis and cell death. J Neurosci 1995;15: 6239–6249.
Keller JN, Pang Z, Geddes JW, et al. Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid beta-peptide: role of the lipid peroxidation product 4-hydroxynonenal. J Neurochem 1997;69:273–284.
Mattson MP, Partin J, Begley JG. Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites. Brain Res 1998;807:167–176.
Mattson MP. Apoptotic and anti-apoptotic synaptic signaling mechanisms. Brain Pathol 2000; 10: 300–312.
Smith JD. Apolipoproteins and aging: emerging mechanisms. Ageing Res Rev 2002;1:345–365.
Mattson MP, Chan SL, Duan W. Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. Physiol Rev 2002;82:637–672.
Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 2003;26:137–146.
Friedland RP, Fritsch T, Smyth KA, et al. Patients with Alzheimer’s disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci USA. 2001;98:3440–3445.
Esler WP, Wolfe MS. A portrait of Alzheimer secretases—new features and familiar faces. Science 2001;293:1449–1454.
Guo Q, Sopher BL, Furukawa K, et al. Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid beta-peptide: involvement of calcium and oxyradicals. J Neurosci 1997;17:4212–4222.
Guo Q, Fu W, Sopher BL, et al. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in PS-1 mutant knock-in mice. Nat Med. 1999;5:101–106.
Chan SL, Culmsee C, Haughey N, Klapper W, Mattson MP. PS-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12. Neurobiol Dis 2002;11:2–19.
Mattson MP, Zhu H, Yu J, Kindy MS. PS-1 mutation increases neuronal vulnerability to focal ischemia in vivo and to hypoxia and glucose deprivation in cell culture: involvement of perturbed calcium homeostasis. J Neurosci 2000; 20:1358–1364.
Pak K, Chan SL, Mattson MP. PS-1 mutation sensitizes oligodendrocytes to glutamate and amyloid toxicities, and exacerbates white matter damage and memory impairment in mice. Neuromolecular Med 2003;3:53–64.
McGeer PL, McGeer EG. Anti-inflammatory drugs in the fight against Alzheimer’s disease. Ann NY Acad Sci 1996;777:213–220.
Benveniste EN, Nguyen VT, O’Keefe GM. Immunological aspects of microglia: relevance to Alzheimer’s disease. Neurochem Int 2001;39:381–391.
Lee J, Chan SL, Mattson MP. Adverse effect of a PS-1 mutation in microglia results in enhanced nitric oxide and inflammatory cytokine responses to immune challenge in the brain Neuromolecular Med. 2002;2:29–45.
Haughey NJ, Mattson MP. Alzheimer’s amyloid beta-peptide enhances ATP/gap junction-mediated calcium-wave propagation in astrocytes. Neuromolecular Med. 2003;3:173–180.
Blanc EM, Keller JN, Fernandez S, Mattson MP. 4-hydroxynonenal, a lipid peroxidation product, impairs glutamate transport in cortical astrocytes. Glia. 1998;22:149–160.
Van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature 2002;415:1030–1034.
Feng R, Rampon C, Tang YP, et al. Deficient neurogenesis in forebrain-specific PS-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron. 2001;32: 911–926.
Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J. Neurochem 2002;83:1509–1524.
Haughey NJ, Liu D, Nath A, Borchard AC, Mattson MP. Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer’s disease. Neuromolecular Med. 2002;1:125–135.
Lee J, Seroogy KB, Mattson MP. Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice. J. Neurochem. 2002;80:539–547.
Kempermann G, Gast D, Gage FH. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann. Neurol. 2002;52: 135–143.
Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25:295–301.
Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J. Neurochem. 2002;82:1367–1375.
Hardy J. Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 1997;20: 154–159.
Mattson MP, Chan SL, Camandola S. Presenilin mutations and calcium signaling defects in the nervous and immune systems. Bioessays 2001;23:733–744.
Cedazo-Minguez A, Cowburn RF. Apolipoprotein E: a major piece in the Alzheimer’s disease puzzle. J. Cell. Mol. Med. 2001;5:254–266.
Miyata M, Smith JD. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat. Genet. 1996;14:55–61.
Pedersen WA, Chan SL, Mattson MP. A mechanism for the neuroprotective effect of apolipoprotein E: isoform-specific modification by the lipid peroxidation product 4-hydroxynonenal. J. Neurochem. 2000;74: 1426–1433.
Hartmann H, Eckert A, Muller WE. Apolipoprotein E and cholesterol affect neuronal calcium signalling: the possible relationship to beta-amyloid neurotoxicity. Biochem. Biophys. Res. Commun. 1994;200:1185–1192.
Tolar M, Keller JN, Chan SL, Mattson MP, Marques MA, Crutcher KA. Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity. J. Neurosci. 1999;19:7100–7110.
Bruce-Keller AJ, Umberger G, McFall R, Mattson MP. Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Ann. Neurol. 1999;45:8–15.
Boegman RJ, Cockhill J, Jhamandas K, Beninger RJ. Excitotoxic lesions of rat basal forebrain: differential effects on choline acetyltransferase in the cortex and amygdala. Neuroscience 1992;51:129–135.
Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990;250:279–282.
Geula C, Wu CK, Saroff D, Lorenzo A, Yuan M, Yankner BA. Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat. Med. 1998; 4:827–831.
Tran MH, Yamada K, Nabeshima T. Amyloid beta-peptide induces cholinergic dysfunction and cognitive deficits: a minireview. Peptides 2002;23:1271–1283.
Stein-Behrens B, Mattson MP, Chang I, Yeh M, Sapolsky RM. Stress exacerbates neuron loss and cytoskeletal pathology in the hippocampus. J. Neurosci. 1994;14:5373–5380.
Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996;274:99–102.
Chapman PF, White GL, Jones MW, et al. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat. Neurosci. 1999;2:271–276.
Arendash GW, King DL, Gordon MN, et al. Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and PS-1 transgenes. Brain Res 2001;891:42–53.
Zaman SH, Parent A, Laskey A, et al. Enhanced synaptic potentiation in transgenic mice expressing presenilin 1 familial Alzheimer’s disease mutation is normalized with a benzodiazepine. Neurobiol. Dis. 2000;7: 54–63.
Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409–421.
Ikegami S, Harada A, Hirokawa N. Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci. Lett. 2000;279:129–132.
Pedersen WA, Culmsee C, Ziegler D, Herman JP, Mattson MP. Aberrant stress response associated with severe hypoglycemia in a transgenic mouse model of Alzheimer’s disease. J. Mol. Neurosci. 1999;13: 159–165.
Sloane PD, Zimmerman S, Suchindran C, et al. The public health impact of Alzheimer’s disease, 2000-2050. Annu. Rev. Public Health 2002;23:213–231.
Zhu H, Guo Q, Mattson MP. Dietary restriction protects hippocampal neurons against the death-promoting action of a PS-1 mutation. Brain Res 1999;842:224–229.
Luchsinger JA, Tang MX, Shea S, Mayeux R. Caloric intake and the risk of Alzheimer disease. Arch. Neurol. 2002;59:1258–1263.
Aarsland D, Cummings JL, Yenner G, Miller B. Relationship of aggressive behavior to other neuropsychiatric symptoms in patients with Alzheimer’s disease. Am. J. Psychiatry 1996;153: 243–247.
Devanand DP, Jacobs DM, Tang MX, et al. The course of psychopathologic features in mild to moderate Alzheimer disease. Arch. Gen. Psychiatry 1997;54:257–263.
Stoppe G, Brandt CA, Staedt JH. Behavioural problems associated with dementia: the role of newer antipsychotics. Drugs Aging 1999;14:41–54.
Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC. Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am. J. Psychiatry 2000;157: 708–714.
Sukonick DL, Pollock BG, Sweet RA, et al. The 5-HTTPR*S/*L polymorphism and aggressive behavior in Alzheimer disease. Arch. Neurol. 2001;58:1425–1428.
Holmes C, Smith H, Ganderton R, et al. Psychosis and aggression in Alzheimer’s disease: the effect of dopamine receptor gene variation. J. Neurol. Neurosurg. Psychiatry 2001;71:777–779.
Mattson MP. Gene-diet interactions in brain aging and neurodegenerative disorders. Ann Intern Med. 2003; 139:441–444.
Mattson MP. Will caloric restriction and folate protect against AD and PD? Neurology. 2003;60: 690–695.
Ingram DK, Weindruch R, Spangler EL, Freeman JR, Walford RL. Dietary restriction benefits learning and motor performance of aged mice. J. Gerontol. 1987;42:78–81.
Guo Z, Ersoz A, Butterfield DA, Mattson MP. Beneficial effects of dietary restriction on cerebral cortical synaptic terminals: preservation of glucose transport and mitochondrial function after exposure to amyloid beta-peptide and oxidative and metabolic insults. J. Neurochem. 2000;75: 314–320.
Mattson MP. Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity. Trends Neurosci. 1998;21:53–57.
Butterfield DA, Drake J, Pocernich C, Castegna A. Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol. Med. 2001;7:548–554.
Selkoe DJ, Schenk D. Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu. Rev. Pharmacol. Toxicol. 2003;43:545–584.
et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature. 2000; 408:979–982.
Mohajeri MH, Saini K, Schultz JG, Wollmer MA, Hock C, Nitsch RM. Passive immunization against beta-amyloid peptide protects central nervous system (CNS) neurons from increased vulnerability associated with an Alzheimer’s disease-causing mutation. J. Biol. Chem. 2002;277: 33012–33017.
Morgan D, Diamond DM, Gottschall PE, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 2000;408:982–985.
Hock C, Konietzko U, Streffer JR, et al. Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron 2003;38:547–554.
Mattson MP, Chan SL. Good and bad amyloid antibodies. Science, in press.
Lanctot KL, Herrmann N, LouLou MM. Correlates of response to acetylcholinesterase inhibitor therapy in Alzheimer’s disease. J. Psychiatry Neurosci. 2003;28:13–26.
Tariot PN, Loy R, Ryan JM, Porsteinsson A, Ismail S. Mood stabilizers in Alzheimer’s disease: symptomatic and neuroprotective rationales. Adv. Drug Deliv. Rev. 2002;54:1567–1577.
Rutten BP, Steinbusch HW, Korr H, Schmitz C. Antioxidants and Alzheimer’s disease: from bench to bedside (and back again). Curr. Opin. Clin. Nutr. Metab. Care 2002;5:645–651.
Aisen PS. The potential of anti-inflammatory drugs for the treatment of Alzheimer’s disease. Lancet Neurol. 2002;1:279–284.
Cholerton B, Gleason CE, Baker LD, Asthana S. Estrogen and Alzheimer’s disease: the story so far. Drugs Aging 2002;19:405–427.
Bush AI. The metallobiology of Alzheimer’s disease. Trends Neurosci. 2003;26:207–214.
Ferris SH. Evaluation of nemantine for the treatment of Alzheimer’s disease. Expert Opin Pharmacother 2003;4:2305–2313.
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© 2005 Humana Press Inc., Totowa, NJ
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Mattson, M.P. (2005). Alzheimer’s Disease. In: Tarazi, F.I., Schetz, J.A. (eds) Neurological and Psychiatric Disorders. Current Clinical Neurology. Humana Press. https://doi.org/10.1385/1-59259-856-0:051
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DOI: https://doi.org/10.1385/1-59259-856-0:051
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