Abstract
Alzheimer’s disease (AD), the leading cause of dementia in the elderly, is an irreversible, progressive neurodegenerative disorder clinically characterized by memory loss and cognitive decline [1], leading invariably to death, usually within 7–10 years after diagnosis. The dominant risk factor for sporadic AD is increasing age.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Khachaturian, Z.S., Diagnosis of Alzheimer’s disease. Arch Neurol, 1985. 42(11):1097–1105.
O’Brien, J., Ames, D., and Burns, A., Dementia (2nd Ed). 2000, Arnold: London.
Jellinger, K., Morphology of Alzheimer’s disease and related disorders, in Alzheimer’s disease: epidemiology, neuropathology, neurochemistry, and clinics. K. Maurer, P. Riederer, and H. Beckmann, Editors. 1990, Springer-Verlag: Berlin. 61–77.
Selkoe, D.J., Alzheimer’s disease: genotypes, phenotypes, and treatments. Science, 1997. 275(5300): 630–631.
Michaelis, M.L., Dobrowsky, R.T., and Li, G., Tau neurofibrillary pathology and microtubule stability. J Mol Neurosci, 2002. 19(3):289–293.
Jellinger, K.A. and Bancher, C., Neuropathology of Alzheimer’s disease: a critical update. J Neural Transm Suppl, 1998. 54:77–95.
Perl, D.P., Neuropathology of Alzheimer’s disease and related disorders. Neurol Clin, 2000. 18(4):847–864.
Geula, C., Wu, C.K., Saroff, D., Lorenzo, A., Yuan, M., and Yankner, B.A., Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat Med, 1998. 4(7):827–831.
Lu, M. and Kosik, K.S., Competition for microtubulebinding with dual expression of tau missense and splice isoforms. Mol Biol Cell, 2001. 12(1):171–184.
Yankner, B.A., Duffy, L.K., and Kirschner, D.A., Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science, 1990. 250(4978):279–282.
Lovestone, S. and Reynolds, C.H., The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. Neuroscience, 1997. 78(2):309–324.
Frank, R.A., Galasko, D., Hampel, H., et al., Biological markers for therapeutic trials in Alzheimer’s disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer’s disease.Neurobiol Aging, 2003. 24(4):521–536.
Geula, C., The early diagnosis of Alzheimer’s disease, in Pathological diagnosis of Alzheimer’s disease. L.F.M. Scinto and K.R. Daffner, Editors. 2000, Humana: Totowa, NJ. 65–82.
Isacson, O., Seo, H., Lin, L., et al., Alzheimer’s disease and Down’s syndrome: roles of APP, trophic factors and ACh. Trends Neurosci, 2002. 25(2):79–84.
Cummings, J.L., Vinters, H.V., Cole, G.M., and Khachaturian, Z.S., Alzheimer’s disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology, 1998. 51(1 Suppl 1): S2–17; discussion S65-17.
Larson, E.B., Edwards, J.K., O’Meara, E., et al., Neuropathologic diagnostic outcomes from a cohort of outpatients with suspected dementia. J Gerontol A Biol Sci Med Sci, 1996. 51(suppl 6):M313–M318.
Petersen, R.C., Mild cognitive impairment: transition between aging and Alzheimer’s disease. Neurologia, 2000. 15(3):93–101.
Petersen, R.C., Smith, G.E., Ivnik, R.J., et al., Apolipoprotein E status as a predictor of the development of Alzheimer’s disease in memoryimpaired individuals. JAMA, 1995. 273:1274–1278.
Petersen, R.C., Smith, G.E., Waring, S.C., et al., Mild cognitive impairment: clinical characterization and outcome. Arch Neurol, 1999. 56:303–308.
Selkoe, D.J., Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev, 2001. 81(2):741–766.
Hardy, J., Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci, 1997. 20(4):154–159.
McLean, C.A., Cherny, R.A., Fraser, F.W., et al., Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neurol, 1999. 46(6):860–866.
Harkany, T., Hortobagyi, T., Sasvari, et al., Neuroprotective approaches in experimental models of beta-amyloid neurotoxicity: relevance to Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry, 1999. 23(6):963–1008.
Harkany, T., Abraham, I., Konya, C., et al., Mechanisms of beta-amyloid neurotoxicity: perspectives of pharmacotherapy. Rev Neurosci, 2000. 11(4):329–382.
Alzheimer, A., Uber eine eijenartige Erkrankung der Hirnride. Allg Z Psychiatr, 1907. 64:146–148.
Perusini, G., Uber klinisch und histologisch eigenartige psychische Erkankungen des spateren Lebensalters, in Histologische und Histolopathologische Arbeiten, F. Nissl, and A. Alzheimer, Editors. 1910, Gustav Fischer: Jena. 297–351.
Kraepelin, E., Das senile und prasenile Irresein, in Psychiatrie: Ein Lehrbuch fur Studierende und Arzte. E. Kraepelin, Editor. 1910, Verlag von Johann Ambrosius Barth: Leipzig. 533–554; 593–632.
Neumann, M.A. and Cohn, R., Incidence of Alzheimer’s disease in a large mental hospital: relation to senile psychosis and psychosis with cerebral arteriosclerosis. Arch Neurol Psychiatr, 1953. 69:615–636.
Rorsman, B., Hagnell, O., and Lanke, J., Prevalence and incidence of senile and multi-infarct dementia in the Lundby study: a comparison between the time periods 1947–1957 and 1957–1972. Neuropsychobiology, 1986. 15:122–129.
Kay, D.W.K., Beamish, P., and Roth, M., Old age mental disorders in Newcastle upon Tyne. Part I: a study of prevalence. Br J Psychiatry, 1964. 110:146–158.
Sjogren, T., Sjogren, H., and Lindgren, G.H., Morbus Alzheimer and morbus Pick: a genetic, clinical and patho-anatomical study. Acta Psychiatr Neurol Scand, 1952. 82(Suppl):1–152.
Larsson, T., Sjogren, T., and Jacobsen, G., Senile dementia: a clinical, sociomedical and genetic study. Acta Psychiatr Scand, 1963. 167(Suppl): 1–259.
Tomlinson, B.E., Blessed, G., and Roth, M., Observations on the brains of non-demented old people. J Neurol Sci, 1968. 7(2):331–356.
Evans, D.A., Funkenstein, H.H., Albert, M.S., et al., Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA, 1989. 262(18):2551–2556.
Davies, P. and Maloney, A.J.F., Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet, 1976. 2:1400–1403.
Scholz, W., Studien zur Pathologie der Hirngefasse. II Die drusige Entartung der Hirnarterien und Capillaren. Z Gesamte Neurol Psychiatr, 1938. 162:694–715.
Pantelakis, S., Un type particulier d’angiopathie senile du systeme nerveux central: l’angiopathie congophile. Topographie et frequence. Monat Psychiatr Neurol, 1954. 128:219–256.
Terry, R.D., Gonatas, N.K., and Weiss, M., Ultrastructural studies in Alzheimer’s presenile dementia. Am J Pathol, 1964. 44:269–287.
Kidd, M., Paired helical filaments in elctron microscopy of Alzheimer’s disease. Nature, 1963. 197:192–193.
Kosik, K.S., Tau protein and neurodegeneration.Mol Neurobiol, 1990. 4(3–4):171–179.
Nukina, N. and Ihara, Y., One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem (Tokyo), 1986. 99(5):1541–1544.
Kosik, K.S., Joachim, C.L., and Selkoe, D.J., Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer’s disease. Proc Natl Acad Sci U S A, 1986. 83(11):4044–4048.
Goedert, M., Wischik, C.M., Crowther, R.A., et al., Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer’s disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A, 1988. 85(11):4051–4055.
Wischik, C.M., Novak, M., Thogersen, H.C., et al., Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer’s disease. Proc Natl Acad Sci U S A, 1988. 85(12):4506–4510.
Kosik, K.S., Duffy, L.K., Dowling, M.M., et al., Microtubule-associated protein 2: monoclonal antibodies demonstrate the selective incorporation of certain epitopes into Alzheimer neurofibrillary tangles. Proc Natl Acad Sci U S A, 1984. 81(24): 7941–7945.
Selkoe, D.J., Ihara, Y., and Salazar, F.J., Alzheimer’s disease: insolubility of partially purified paired helical filaments in sodium dodecyl sulfate and urea. Science, 1982. 215(4537):1243–1245.
Virchow, R., Zur cellulosefrage, in Virchows Arch Pathol Anat Physiol, 1854. 416–426.
Glenner, G.G. and Wong, C.W., Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun, 1984. 120(3):885–890.
Glenner, G.G., Wong, C.W., Quaranta, V., and Eanes, E.D., The amyloid deposits in Alzheimer’s disease: their nature and pathogenesis. Appl Pathol, 1984. 2(6):357–369.
Masters, C.L., Simms, G., Weinman, N.A., et al., Amyloid plaque core protein in Alzheimer’s disease and Down syndrome. Proc Natl Acad Sci U S A, 1985. 82(12):4245–4249.
St George-Hyslop, P.H., Tanzi, R.E., Polinsky, R.J., et al.., The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science, 1987. 235(4791):885–890.
Tanzi, R.E., St George-Hyslop, P.H., Haines, J.L., et al., The genetic defect in familial Alzheimer’s disease is not tightly linked to the amyloid beta-protein gene. Nature, 1987. 329(6135):156–157.
Van Broeckhoven, C., Genthe, A.M., Vandenberghe, A., et al., Failure of familial Alzheimer’s disease to segregate with the A4-amyloid gene in several European families. Nature, 1987. 329(6135):153–155.
Kang, J., Lemaire, H.G., Unterbeck, A., Salbaum, J.M., et al., The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature, 1987. 325(6106):733–736.
Tanzi, R.E., Gusella, J.F., Watkins, P.C., et al., Amyloid beta protein gene:cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science, 1987. 235(4791):880–884.
Robakis, N.K., Wisniewski, H.M., Jenkins, E.C., et al., Chromosome 21q21 sublocalisation of gene encoding beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques of people with Alzheimer’s disease and Down syndrome. Lancet, 1987. 1(8529):384–385.
Van Broeckhoven, C., Haan, J., Bakker, E., et al., Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science, 1990. 248(4959):1120–1122.
Levy, E., Carman, M.D., Fernandez-Madrid, I.J., et al., Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science, 1990. 248(4959):1124–1126.
Goate, A., Chartier-Harlin, M.C., Mullan, M., et al., Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature, 1991. 349(6311):704–706.
Citron, M., Oltersdorf, T., Haass, C., et al., Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature, 1992. 360(6405):672–674.
Schellenberg, G.D., Bird, T.D., Wijsman, E.M., et al., Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14. Science, 1992. 258(5082):668–671.
Mullan, M., Houlden, H., Windelspecht, M., et al., A locus for familial early-onset Alzheimer’s disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene. Nat Genet, 1992. 2(4):340–342.
St George-Hyslop, P., Haines, J., Rogaev, E., et al., Genetic evidence for a novel familial Alzheimer’s disease locus on chromosome 14. Nat Genet, 1992. 2(4):330–334.
Van Broeckhoven, C., Backhovens, H., Cruts, M., et al., Mapping of a gene predisposing to early-onset Alzheimer’s disease to chromosome 14q24.3. Nat Genet, 1992. 2(4):335–339.
Yankner, B.A., Dawes, L.R., Fisher, S., et al., Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science, 1989. 245(4916):417–420.
Pike, C.J., Walencewicz, A.J., Glabe, C.G., and Cotman, C.W., In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res, 1991. 563(1–2):311–314.
Pike, C.J., Walencewicz, A.J., Glabe, C.G., and Cotman, C.W., Aggregation-related toxicity of synthetic beta-amyloid protein in hippocampal cultures. Eur J Pharmacol, 1991. 207(4):367–368.
Bush, A.I., Multhaup, G., Moir, R.D., et al., A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer’s disease. J Biol Chem, 1993. 268(22):16109–16112.
Bush, A.I., Pettingell, W.H., Multhaup, G., Paradis, M., et al., Rapid induction of Alzheimer Aβ amyloid formation by zinc. Science, 1994. 265(5177):1464–1467.
Strittmatter, W.J., Saunders, A.M., Schmechel, D., et al., Apolipoprotein E: high-avidity binding to betaamyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease. Proc Natl Acad Sci U S A, 1993. 90(5):1977–1981.
Corder, E.H., Saunders, A.M., Strittmatter, W.J., et al., Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 1993. 261(5123):921–923.
Schmechel, D.E., Saunders, A.M., Strittmatter, W.J., et al., Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer’s disease. Proc Natl Acad Sci U S A, 1993. 90(20):9649–9653.
Sherrington, R., Rogaev, E.I., Liang, Y., et al., Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature, 1995. 375(6534): 754–760.
Levy-Lahad, E., Wasco, W., Poorkaj, P., et al., Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science, 1995. 269(5226): 973–977.
Scheuner, D., Eckman, C., Jensen, M., et al., Secreted amyloid beta-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. Nat Med, 1996. 2(8):864–870.
Selkoe, D.J., Alzheimer’s disease is a synaptic failure. Science, 2002. 298(5594):789–791.
Selkoe, D.J., Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci, 2000. 924:17–25.
Selkoe, D.J., The genetics and molecular pathology of Alzheimer’s disease: roles of amyloid and the presenilins. Neurol Clin, 2000. 18(4):903–922.
Masters, C.L. and Beyreuther, K., Alzheimer’s disease. BMJ, 1998. 316(7129):446–448.
Masters, C.L. and Beyreuther, K., Molecular neuropathology of Alzheimer’s disease. Arzneimittelforschung, 1995. 45(3A):410–412.
Bartus, R.T., Dean, R.L., 3rd, Beer, B., and Lippa, A.S., The cholinergic hypothesis of geriatric memory dysfunction. Science, 1982. 217(4558):408–414.
Bartus, R.T. and Emerich, D.F., Cholinergic markers in Alzheimer’s disease. JAMA, 1999. 282(23):2208–2209.
Masters, C.L. and Beyreuther, K., Henryk M. Wisniewski and the amyloid theory of Alzheimer’s disease. J Alzheimers Dis, 2001. 3(1):83–86.
Martins, R.N., Robinson, P.J., Chleboun, J.O., et al., The molecular pathology of amyloid deposition in Alzheimer’s disease. Mol Neurobiol, 1991. 5(2–4): 389–398.
Beyreuther, K. and Masters, C.L., Amyloid precursor protein (APP) and beta A4 amyloid in the etiology of Alzheimer’s disease: precursor-product relationships in the derangement of neuronal function. Brain Pathol., 1991. 1(4):241–251.
Cappai, R. and White, A.R., Amyloid beta. Int J Biochem Cell Biol, 1999. 31(9):885–889.
Haass, C., Koo, E.H., Mellon, A., et al., Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature, 1992. 357(6378):500–503.
Seubert, P., Vigo-Pelfrey, C., Esch, F., et al., Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature, 1992. 359(6393):325–327.
Shoji, M., Golde, T.E., Ghiso, J., et al.., Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science, 1992. 258(5079): 126–129.
Harper, J.D. and Lansbury, P.T., Jr., Models of amyloid seeding in Alzheimer’s disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem, 1997. 66:385–407.
Soto, C., Castano, E.M., Frangione, B., and Inestrosa, N.C., The alpha-helical to beta-strand transition in the amino-terminal fragment of the amyloid beta-peptide modulates amyloid formation. J Biol Chem, 1995. 270(7):3063–3067.
Inoue, S., Kuroiwa, M., Tan, R., and Kisilevsky, R., A high resolution ultrastructural comparison of isolated and in situ murine AA amyloid fibrils. Amyloid, 1998. 5(2):99–110.
Cohen, A.S., Shirahama, T., and Skinner, M., Electron microscopy of amyloid, in Electron Microscopy of Proteins. J.R. Harris, Editor. 1982, Academic Press: London. 165–205.
Westermark, P., Benson, M.D., Buxbaum, J.N., et al., Amyloid fibril protein nomenclature-2002. Amyloid, 2002. 9(3):197–200.
Westermark, P., Araki, S., Benson, M.D., et al., Nomenclature of amyloid fibril proteins. Report from the meeting of the International Nomenclature Committee on Amyloidosis, August 8–9, 1998. Part 1. Amyloid, 1999. 6(1):63–66.
Stevens, F.J. and Kisilevsky, R., Immunoglobulin light chains, glycosaminoglycans, and amyloid. Cell Mol Life Sci, 2000. 57(3):441–449.
Perry, E.K., Tomlinson, B.E., Blessed, G., et al.., Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J, 1978. 2(6150):1457–1459.
Blessed, G., Tomlinson, B.E., and Roth, M., The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry, 1968. 114(512):797–811.
Yamaguchi, H., Hirai, S., Morimatsu, M., et al., Diffuse type of senile plaques in the brains of Alzheimer-type dementia. Acta Neuropathol (Berl), 1988. 77(2):113–119.
Skovronsky, D.M., Doms, R.W., and Lee, V.M., Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture. J Cell Biol, 1998. 141(4):1031–1039.
Bush, A.I., The metallobiology of Alzheimer’s disease. Trends Neurosci, 2003. 26(4):207–214.
Haass, C., Schlossmacher, M.G., Hung, A.Y., et al., Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature, 1992. 359(6393):322–325.
Mega, M.S., Chu, T., Mazziotta, J.C., et al., Mapping biochemistry to metabolism: FDG-PET and amyloid burden in Alzheimer’s disease. Neuroreport, 1999. 10(14):2911–2917.
Greenberg, S.M., Rebeck, G.W., et al., Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol, 1995. 38(2): 254–259.
McLean, C.A., Beyreuther, K., and Masters, C.L., Amyloid Abeta levels in Alzheimer’s disease-A diagnostic tool and the key to understanding the natural history of Abeta? J Alzheimers Dis, 2001. 3(3):305–312.
Naslund, J., Haroutunian, V., Mohs, R., et al., Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA, 2000. 283(12):1571–1577.
Lue, L.F., Kuo, Y.M., Roher, A.E., et al., Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol, 1999. 155(3):853–862.
Wang, J., Dickson, D.W., Trojanowski, J.Q., and Lee, V.M., The levels of soluble versus insoluble brain Aβ distinguish Alzheimer’s disease from normal and pathologic aging. ExNeurol, 1999. 158(2):328–337.
Braak, H. and Braak, E., Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl), 1991. 82(4):239–259.
Hardy, J. and Selkoe, D.J., The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 2002. 297(5580): 353–356.
Price, J.L. and Morris, J.C., Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol, 1999. 45(3):358–368.
Lemere, C.A., Blusztajn, J.K., Yamaguchi, H., et al., Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis, 1996. 3(1):16–32.
Mann, D.M., Yates, P.O., Marcyniuk, B., and Ravindra, C.R., The topography of plaques and tangles in Down’s syndrome patients of different ages. Neuropathol Appl Neurobiol, 1986. 12(5):447–457.
Selkoe, D.J., The molecular pathology of Alzheimer’s disease. Neuron, 1991. 6(4):487–498.
Hardy, J.A. and Higgins, G.A., Alzheimer’s disease: the amyloid cascade hypothesis. Science, 1992. 256(5054):184–185.
Checler, F. and Vincent, B., Alzheimer’s and prion diseases: distinct pathologies, common proteolytic denominators.Trends Neurosci, 2002. 25(12):616–620.
Robinson, S.R. and Bishop, G.M., The search for an amyloid solution. Science, 2002. 298(5595):962–964; author reply 962–964.
Robinson, S.R. and Bishop, G.M., Abeta as a bioflocculant: implications for the amyloid hypothesis of Alzheimer’s disease. Neurobiol Aging, 2002. 23(6):1051–1072.
Mudher, A. and Lovestone, S., Alzheimer’s disease-do tauists and baptists finally shake hands? Trends Neurosci, 2002. 25(1):22–26.
Selkoe, D.J., Translating cell biology into therapeutic advances in Alzheimer’s disease.Nature, 1999. 399(6738 Suppl):A23–31.
St George-Hyslop, P.H., Genetic factors in the genesis of Alzheimer’s disease. Ann N Y Acad Sci, 2000. 924:1–7.
Haass, C., Hung, A.Y., Selkoe, D.J., and Teplow, D.B., Mutations associated with a locus for familial Alzheimer’s disease result in alternative processing of amyloid beta-protein precursor. J Biol Chem, 1994. 269(26):17741–17748.
Cai, X.D., Golde, T.E., and Younkin, S.G., Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science, 1993. 259(5094):514–516.
Suzuki, N., Cheung, T.T., Cai, X.D., et al., An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science, 1994. 264(5163): 1336–1340.
Citron, M., Vigo-Pelfrey, C., Teplow, D.B., et al., Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer’s disease mutation. Proc Natl Acad Sci U S A, 1994. 91(25):11993–11997.
Miklossy, J., Taddei, K., Suva, D., et al.., Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer’s disease. Neurobiol Aging, 2003. 24(5):655–662.
Rogaev, E.I., Sherrington, R., Rogaeva, E.A., et al.., Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature, 1995. 376(6543):775–778.
Thinakaran, G., Teplow, D.B., Siman, R., et al., Metabolism of the “Swedish” amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the “beta-secretase” site occurs in the golgi apparatus. J Biol Chem, 1996. 271(16):9390–9397.
Citron, M., Westaway, D., Xia, W., Carlson, G., et al.., Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med, 1997. 3(1):67–72.
Duff, K., Eckman, C., Zehr, C., et al.., Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature, 1996. 383(6602):710–713.
Poirier, J., Davignon, J., Bouthillier, D., et al., Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet, 1993. 342(8873):697–699.
Borchelt, D.R., Thinakaran, G., Eckman, C.B., et al., Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron, 1996. 17(5):1005–1013.
Polvikoski, T., Sulkava, R., Haltia, M., et al., Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med, 1995. 333(19):1242–1247.
Rebeck, G.W., Reiter, J.S., Strickland, D.K., and Hyman, B.T., Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron, 1993. 11(4):575–580.
Hyman, B.T., West, H.L., Rebeck, G.W., et al., Quantitative analysis of senile plaques in Alzheimer’s disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome). Proc Natl Acad Sci U S A, 1995. 92(8):3586–3590.
Mehta, N.D., Refolo, L.M., Eckman, C., et al., Increased Abeta42(43) from cell lines expressing presenilin 1 mutations. Ann Neurol, 1998. 43(2): 256–258.
Beyreuther, K., Dyrks, T., Hilbich, C., et al., Amyloid precursor protein (APP) and beta A4 amyloid in Alzheimer’s disease and Down syndrome. Prog Clin Biol Res, 1992. 379:159–182.
Masters, C.L. and Beyreuther, K.T., The pathology of the amyloid A4 precursor of Alzheimer’s disease. Ann Med, 1989. 21(2):89–90.
Dyrks, T., Weidemann, A., Multhaup, G., et al., Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer’s disease. EMBO J, 1988. 7(4):949–957.
Goldgaber, D., Lerman, M.I., McBride, O.W., et al., Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science, 1987. 235(4791):877–880.
Robakis, N.K., Ramakrishna, N., Wolfe, G., and Wisniewski, H.M., Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci U S A, 1987. 84(12):4190–4194.
Olson, M.I. and Shaw, C.M., Presenile dementia and Alzheimer’s disease in mongolism. Brain, 1969. 92(1):147–156.
Querfurth, H.W., Wijsman, E.M., St George-Hyslop, P.H., and Selkoe, D.J., Beta APP mRNA transcription is increased in cultured fibroblasts from the familial Alzheimer’s disease-1 family. Brain Res Mol Brain Res, 1995. 28(2):319–337.
Turner, P.R., O’Connor, K., Tate, W.P., and Abraham, W.C., Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol, 2003. 70(1):1–32.
Kuentzel, S.L., Ali, S.M., Altman, R.A., et al., The Alzheimer beta-amyloid protein precursor/protease nexin-II is cleaved by secretase in a trans-Golgi secretory compartment in human neuroglioma cells. Biochem J, 1993. 295(Pt 2):367–378.
Citron, M., Identifying proteases that cleave AP. Ann N Y Acad Sci, 2000. 920:192–196.
Mullan, M., Crawford, F., Axelman, K., et al., A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of betaamyloid. Nat Genet, 1992. 1(5):345–347.
Hardy, J., Framing beta-amyloid. Nat Genet, 1992. 1(4):233–234.
Hendriks, L., van Duijn, C.M., Cras, P., et al., Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet, 1992. 1(3):218–221.
Wisniewski, T., Ghiso, J., and Frangione, B., Peptides homologous to the amyloid protein of Alzheimer’s disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem Biophys Res Commun, 1991. 179(3):1247–1254.
Citron, M., Secretases as targets for the treatment of Alzheimer’s disease. Mol Med Today,2000. 6(10): 392–397.
Seubert, P., Oltersdorf, T., Lee, M.G., et al.., Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature, 1993. 361(6409):260–263.
Citron, M., Haass, C., and Selkoe, D.J., Production of amyloid-beta-peptide by cultured cells: no evidence for internal initiation of translation at Met596. Neurobiol Aging, 1993. 14(6):571–573.
Muller, U. and Kins, S., APP on the move. Trends Mol Med, 2002. 8(4):152–155.
Andrews, N.C., Mining copper transport genes. Proc Natl Acad Sci U S A, 2001. 98(12):6543–6545.
Barnham, K.J., Masters, C.L., and Bush, A.I., Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov, 2004. 3(3):205–214.
Culotta, V.C., Klomp, L.W., Strain, J., et al.., The copper chaperone for superoxide dismutase. J Biol Chem, 1997. 272(38):23469–23472.
Waggoner, D.J., Bartnikas, T.B., and Gitlin, J.D., The role of copper in neurodegenerative disease. Neurobiol Dis, 1999. 6(4):221–230.
Maynard, C.J., Cappai, R., Volitakis, I., et al., Overexpression of Alzheimer’s disease amyloidbeta opposes the age-dependent elevations of brain copper and iron. J Biol Chem, 2002. 277(47): 44670–44676.
White, A.R., Reyes, R., Mercer, J.F., et al., Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain Res, 1999. 842(2):439–444.
Bayer, T.A., Schafer, S., Simons, A., et al., Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc Natl Acad Sci U S A, 2003. 100(24):14187–14192.
Phinney, A.L., Drisaldi, B., Schmidt, S.D., et al., In vivo reduction of amyloid-beta by a mutant copper transporter. Proc Natl Acad Sci U S A, 2003. 100(24):14193–14198.
Borchardt, T., Camakaris, J., Cappai, R., Masters, C.L., Beyreuther, K., and Multhaup, G., Copper inhibits beta-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursorprotein secretion. Biochem J, 1999. 344(Pt 2):461–467.
Barnham, K.J., McKinstry, W.J., Multhaup, G., et al., Structure of the Alzheimer’s disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J Biol Chem, 2003. 278(19):17401–17407.
De Strooper, B., Saftig, P., Craessaerts, K., et al., Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature, 1998. 391(6665):387–390.
Wolfe, M.S., Xia, W., Ostaszewski, B.L., et al., Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature, 1999. 398(6727):513–517.
Kwok, J.B., Taddei, K., Hallupp, M., et al., Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer’s disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport, 1997. 8(6):1537–1542.
Crook, R., Verkkoniemi, A., Perez-Tur, J., et al., A variant of Alzheimer’s disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med, 1998. 4(4):452–455.
Houlden, H., Baker, M., McGowan, E., et al., Variant Alzheimer’s disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol, 2000. 48(5):806–808.
Verkkoniemi, A., Kalimo, H., Paetau, A., et al., Variant Alzheimer’s disease with spastic paraparesis: neuropathological phenotype. J Neuropathol Exp Neurol, 2001. 60(5):483–492.
Smith, M.J., Kwok, J.B., McLean, C.A., et al., Variable phenotype of Alzheimer’s disease with spastic paraparesis. Ann Neurol, 2001.49(1):125–129.
Kovacs, D.M., Fausett, H.J., Page, K.J., et al., Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat Med, 1996. 2(2):224–229.
Kimberly, W.T., Xia, W., Rahmati, T., et al., The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. J Biol Chem, 2000. 275(5):3173–3178.
Takashima, A., Murayama, M., Murayama, O., et al., Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc Natl Acad Sci U S A, 1998. 95(16):9637–9641.
Buxbaum, J.D., Choi, E.K., Luo, Y., et al., Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment. Nat Med, 1998. 4(10):1177–1181.
Shinozaki, K., Maruyama, K., Kume, H., et al., The presenilin 2 loop domain interacts with the mu-calpain C-terminal region. Int J Mol Med, 1998. 1(5): 797–799.
Drouet, B., Pincon-Raymond, M., Chambaz, J., and Pillot, T., Molecular basis of Alzheimer’s disease. Cell Mol Life Sci, 2000. 57(5):705–715.
Wolozin, B., Alexander, P., and Palacino, J., Regulation of apoptosis by presenilin 1. Neurobiol Aging, 1998. 19(1 Suppl): S23–27.
Guo, Q., Fu, W., Xie, J., et al., Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer’s disease. Nat Med, 1998.4(8):957–962.
Bertram, L., Blacker, D., Mullin, K., et al., Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science, 2000. 290(5500):2302–2303.
Myers, A., Holmans, P., Marshall, H., et al. Susceptibility locus for Alzheimer’s disease on chromosome 10. Science, 2000. 290(5500):2304–2305.
Wavrant-DeVrieze, F., Lambert, J.C., Stas, L., et al., Association between coding variability in the LRP gene and the risk of late-onset Alzheimer’s disease. Hum Genet, 1999. 104(5):432–434.
Ertekin-Taner, N., Graff-Radford, N., Younkin, L.H., et al., Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Science, 2000. 290(5500):2303–2304.
Olson, J.M., Goddard, K.A., and Dudek, D.M., The amyloid precursor protein locus and very-late-onset Alzheimer’s disease. Am J Hum Genet, 2001. 69(4):895–899.
Saunders, A.M., Strittmatter, W.J., Schmechel, D., et al., Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology, 1993. 43(8):1467–1472.
Rocchi, A., Pellegrini, S., Siciliano, G., and Murri, L., Causative and susceptibility genes for Alzheimer’s disease: a review. Brain Res Bull, 2003. 61(1):1–24.
Marques, M.A. and Crutcher, K.A., Apolipoprotein E-related neurotoxicity as a therapeutic target for Alzheimer’s disease. J Mol Neurosci, 2003. 20(3): 327–337.
Ramassamy, C., Krzywkowski, P., Averill, D., et al., Impact of apoE deficiency on oxidative insults and antioxidant levels in the brain. Brain Res Mol Brain Res, 2001. 86(1–2):76–83.
Lee, Y., Aono, M., Laskowitz, D., et al., Apolipoprotein E protects against oxidative stress in mixed neuronal-glial cell cultures by reducing glutamate toxicity. Neurochem Int, 2004. 44(2):107–118.
Ramassamy, C., Averill, D., Beffert, U., et al.., Oxidative insults are associated with apolipoprotein E genotype in Alzheimer’s disease brain. Neurobiol Dis, 2000. 7(1):23–37.
Beffert, U. and Poirier, J., ApoE associated with lipid has a reduced capacity to inhibit beta-amyloid fibril formation. Neuroreport, 1998. 9(14):3321–3323.
Hu, J., LaDu, M.J., and Van Eldik, L.J., Apolipoprotein E attenuates beta-amyloid-induced astrocyte activation. J Neurochem, 1998. 71(4): 1626–1634.
Mayeux, R., Saunders, A.M., Shea, S., et al., Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease: Alzheimer’s Disease Centers Consortium on Apolipoprotein E and Alzheimer’s Disease. N Engl J Med, 1998. 338(8):506–511.
St George-Hyslop, P., McLachlan, D.C., Tsuda, T., et al., Alzheimer’s disease and possible gene interaction. Science, 1994. 263(5146):537.
Schupf, N., Kapell, D., Lee, J.H., et al., Onset of dementia is associated with apolipoprotein E epsilon4 in Down’s syndrome. Ann Neurol, 1996. 40(5):799–801.
Kalaria, R.N., Small vessel disease and Alzheimer’s dementia: pathological considerations. Cerebrovasc Dis, 2002. 13(Suppl 2):48–52.
de Figueiredo, R.J., Oten, R., Su, J., and Cotman, C.W., Amyloid deposition in cerebrovascular angiopathy. Ann N Y Acad Sci, 1997. 826:463–471.
Villemagne, V.L., Rowe, C.C., Macfarlane, S., et al. Imaginem Oblivionis: The prospects of neuroimaging for early detection of Alzheimer’s disease. J Clin Neurosci, 2005. 12:221–230.
Jordan, J., Galindo, M.F., Miller, R.J., et al., Isoform-specific effect of apolipoprotein E on cell survival and beta-amyloid-induced toxicity in rat hippocampal pyramidal neuronal cultures. J Neurosci, 1998. 18(1):195–204.
Moir, R.D., Atwood, C.S., Romano, D.M., et al., Differential effects of apolipoprotein E isoforms on metal-induced aggregation of A beta using physiological concentrations. Biochemistry, 1999. 38(14): 4595–4603.
Games, D., Adams, D., Alessandrini, R., et al.., Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature, 1995. 373(6514):523–527.
Masliah, E., Sisk, A., Mallory, M., Mucke, L., et al., Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer’s disease. J Neurosci, 1996. 16(18):5795–5811.
Hsiao, K., Chapman, P., Nilsen, S., et al., Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science, 1996. 274(5284):99–102.
Irizarry, M.C., McNamara, M., Fedorchak, K., et al., APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol, 1997. 56(9):965–973.
Irizarry, M.C., Soriano, F., McNamara, M., et al., Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci, 1997. 17(18):7053–7059.
Poorkaj, P., Bird, T.D., Wijsman, E., et al., Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol, 1998. 43(6):815–825.
Hutton, M., Lendon, C.L., Rizzu, P., et al., Association of missense and 5-splice-site mutations in tau with the inherited dementia FTDP-17. Nature, 1998. 393(6686):702–705.
Spillantini, M.G., Bird, T.D., and Ghetti, B., Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol, 1998. 8(2):387–402.
Spillantini, M.G. and Goedert, M., Tau protein pathology in neurodegenerative diseases. Trends Neurosci, 1998. 21(10):428–433.
Hardy, J., Duff, K., Hardy, K.G., et al., Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau.Nat Neurosci, 1998. 1(5):355–358.
Rapoport, M., Dawson, H.N., Binder, L.I., et al., Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A, 2002. 99(9):6364–6369.
Terry, R.D., Masliah, E., and Hansen, L.A., Structural basis of the cognitive alterations in Alzheimer’s disease, in Alzheimer’s disease. R.D. Terry, R. Katzman, and K.L. Bick, Editors. 1994, Raven Press: New York.
Wisniewski, K.E., Dalton, A.J., McLachlan, C., et al.., Alzheimer’s disease in Down’s syndrome: clinicopathologic studies. Neurology, 1985. 35(7): 957–961.
Lippa, C.F., Nee, L.E., Mori, H., and St George-Hyslop, P., Abeta-42 deposition precedes other changes in PS-1 Alzheimer’s disease. Lancet, 1998. 352(9134):1117–1118.
Lewis, J., Dickson, D.W., Lin, W.L., et al., Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and AP. Science, 2001. 293(5534):1487–1491.
Bales, K.R., Verina, T., Dodel, R.C., et al., Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet, 1997. 17(3): 263–264.
Roher, A.E., Chaney, M.O., Kuo, Y.M., et al., Morphology and toxicity of Abeta-(1-42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer’s disease. J Biol Chem, 1996. 271(34):20631–20635.
Walsh, D.M., Klyubin, I., Fadeeva, J.V., et al., Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 2002. 416(6880):535–539.
Harper, J.D., Wong, S.S., Lieber, C.M., and Lansbury, P.T., Jr., Assembly of A beta amyloid protofibrils: an in vitro model for a possible early event in Alzheimer’s disease. Biochemistry, 1999. 38(28):8972–8980.
Pike, C.J., Burdick, D., Walencewicz, A.J., et al., Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci, 1993. 13(4):1676–1687.
Lorenzo, A. and Yankner, B.A., Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci U S A, 1994. 91(25):12243–12247.
Curtain, C.C., Ali, F., Volitakis, I., et al.., Alzheimer’s disease amyloid-β binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J. Biol. Chem, 2001. 276(23):20466–20473.
Bush, A.I. and Goldstein, L.E., Specific metalcatalysed protein oxidation reactions in chronic degenerative disorders of ageing: focus on Alzheimer’s disease and age-related cataracts. Novartis Found Symp, 2001. 235:26–38; discussion 38-43.
Cuajungco, M.P., Goldstein, L.E., Nunomura, A., et al., Evidence that the β-amyloid plaques of Alzheimer’s disease represent the redox-silencing and entombment of Aβ by zinc. J Biol Chem, 2000. 275(26):19439–19442.
Lambert, M.P., Barlow, A.K., Chromy, B.A., et al., Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A, 1998. 95(11):6448–6453.
Hartley, D.M., Walsh, D.M., Ye, C.P., et al., Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci, 1999. 19(20):8876–8884.
Hsia, A.Y., Masliah, E., McConlogue, L., et al., Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci U S A, 1999. 96(6):3228–3233.
Mucke, L., Masliah, E., Yu, G.Q., et al., High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci, 2000. 20(11):4050–4058.
Reiter, R.J., Oxidative processes and antioxidative defense mechanisms in the aging brain. FASEB J, 1995. 9(7):526–533.
Tomidokoro, Y., Ishiguro, K., Harigaya, Y., et al., Abeta amyloidosis induces the initial stage of tau accumulation in APP(Sw) mice. Neurosci Lett, 2001. 299(3):169–172.
Zheng, W.H., Bastianetto, S., Mennicken, F., et al., Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience, 2002. 115(1):201–211.
Parihar, M.S. and Hemnani, T., Alzheimer’s disease pathogenesis and therapeutic interventions. J Clin Neurosci, 2004. 11(5):456–467.
Vajda, F.J., Neuroprotection and neurodegenerative disease. J Clin Neurosci, 2002. 9(1):4–8.
Saez, T.E., Pehar, M., Vargas, M., et al., Astrocytic nitric oxide triggers tau hyperphosphorylation in hippocampal neurons. In Vivo, 2004. 18(3):275–280.
Multhaup, G., Ruppert, T., Schlicksupp, A., et al., Reactive oxygen species and Alzheimer’s disease. Biochem Pharmacol, 1997. 54(5):533–539.
Perry, G., Taddeo, M.A., Nunomura, A., et al., Comparative biology and pathology of oxidative stress in Alzheimer and other neurodegenerative diseases: beyond damage and response. Comp Biochem Physiol C Toxicol Pharmacol, 2002. 133(4):507–513.
Prasad, K.N., Hovland, A.R., Cole, W.C., et al., Multiple antioxidants in the prevention and treatment of Alzheimer’s disease: analysis of biologic rationale. Clin Neuropharmacol, 2000. 23(1):2–13.
Schippling, S., Kontush, A., Arlt, S., et al., Increased lipoprotein oxidation in Alzheimer’s disease. Free Radic Biol Med, 2000. 28(3):351–360.
Lyras, L., Cairns, N.J., Jenner, A., et al., An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease. J Neurochem, 1997. 68(5):2061–2069.
Smith, C.D., Carney, J.M., Starke-Reed, P.E., et al., Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer’s disease. Proc Natl Acad Sci U S A, 1991. 88(23):10540–10543.
Smith, M.A., Sayre, L.M., Vitek, M.P., et al., Early AGEing and Alzheimer’s. Nature, 1995. 374(6520):316.
Montine, K.S., Olson, S.J., Amarnath, V., et al., Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer’s disease is associated with inheritance of APOE4. Am J Pathol, 1997. 150(2):437–443.
Chang, J.Y., Chavis, J.A., Liu, L.Z., and Drew, P.D., Cholesterol oxides induce programmed cell death in microglial cells. Biochem Biophys Res Commun, 1998. 249(3):817–821.
Bernheimer, A.W., Robinson, W.G., Linder, R., et al., Toxicity of enzymically-oxidized low-density lipoprotein. Biochem Biophys Res Commun, 1987. 148(1):260–266.
Allen, R.G. and Tresini, M., Oxidative stress and gene regulation. Free Radic Biol Med, 2000. 28(3): 463–499.
Dizdaroglu, M., Oxidative damage to DNA in mammalian chromatin. Mutat Res, 1992. 275(3–6): 331–342.
Mattson, M.P., Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol, 2000. 1(2):120–129.
Mark, R.J., Fuson, K.S., and May, P.C., Characterization of 8-epiprostaglandin F2alpha as a marker of amyloid beta-peptide-induced oxidative damage. J Neurochem, 1999. 72(3):1146–1153.
Lovell, M.A., Ehmann, W.D., Butler, S.M., and Markesbery, W.R., Elevated thiobarbituric acidreactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology, 1995. 45(8):1594–1601.
Good, P.F., Werner, P., Hsu, A., et al., Evidence of neuronal oxidative damage in Alzheimer’s disease. Am J Pathol, 1996. 149(1):21–28.
Smith, M.A., Perry, G., Richey, P.L., et al., Oxidative damage in Alzheimer’s. Nature, 1996. 382(6587):120–121.
Love, S., Barber, R., and Wilcock, G.K., Apoptosis and expression of DNA repair proteins in ischaemic brain injury in man. Neuroreport, 1998. 9(6):955–959.
Mecocci, P., MacGarvey, U., and Beal, M.F., Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol, 1994. 36(5):747–751.
Selley, M.L., Close, D.R., and Stern, S.E., The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer’s disease. Neurobiol Aging, 2002. 23(3): 383–388.
Butterfield, D.A., Castegna, A., Lauderback, C.M., and Drake, J., Evidence that amyloid beta-peptideinduced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol Aging, 2002. 23(5):655–664.
Arlt, S., Beisiegel, U., and Kontush, A., Lipid peroxidation in neurodegeneration: new insights into Alzheimer’s disease. Curr Opin Lipidol, 2002. 13(3):289–294.
Keller, J.N., Pang, Z., Geddes, J.W., 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(1):273–284.
Mark, R.J., Hensley, K., Butterfield, D.A., and Mattson, M.P., Amyloid beta-peptide impairs ionmotive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death. J Neurosci, 1995. 15(9):6239–6249.
Tamagno, E., Robino, G., Obbili, A., et al., H2O2 and 4-hydroxynonenal mediate amyloid betainduced neuronal apoptosis by activating JNKs and p38MAPK. Exp Neurol, 2003. 180(2):144–155.
Lewen, A., Matz, P., and Chan, P.H., Free radical pathways in CNS injury. J Neurotrauma, 2000. 17(10):871–890.
Suzuki, Y.J., Forman, H.J., and Sevanian, A., Oxidants as stimulators of signal transduction. Free Radic Biol Med, 1997. 22(1–2):269–285.
Neill, S., Desikan, R., and Hancock, J., Hydrogen peroxide signalling. Curr Opin Plant Biol, 2002. 5(5):388–395.
Ermak, G. and Davies, K.J., Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol, 2002. 38(10):713–721.
LaFerla, F.M., Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci, 2002. 3(11):862–872.
Gibson, G.E., Interactions of oxidative stress with cellular calcium dynamics and glucose metabolism in Alzheimer’s disease. Free Radic Biol Med, 2002. 32(11):1061–1070.
Mattson, M.and Chan, S.L., Neuronal and glial calcium signaling in Alzheimer’s disease. Cell Calcium, 2003. 34(4–5):385–397.
Zemlan, F.P., Thienhaus, O.J., and Bosmann, H.B., Superoxide dismutase activity in Alzheimer’s disease: possible mechanism for paired helical filament formation. Brain Res, 1989. 476(1):160–162.
Pappolla, M.A., Omar, R.A., Kim, K.S., and Robakis, N.K., Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer’s disease. Am J Pathol, 1992. 140(3):621–628.
Gabbita, S.P., Lovell, M.A., and Markesbery, W.R., Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem, 1998. 71(5): 2034–2040.
Yamamoto, K., Ishikawa, T., Sakabe, T., et al., The hydroxyl radical scavenger Nicaraven inhibits glutamate release after spinal injury in rats. Neuroreport, 1998. 9(7):1655–1659.
Law, A., Gauthier, S., and Quirion, R., Say NO to Alzheimer’s disease: the putative links between nitric oxide and dementia of the Alzheimer’s type. Brain Res Brain Res Rev, 2001. 35(1):73–96.
Parks, J.K., Smith, T.S., Trimmer, P.A., et al., Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxidesynthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. J Neurochem, 2001. 76(4):1050–1056.
Blanchard, B.J., Chen, A., Rozeboom, L.M., et al., Efficient reversal of Alzheimer’s disease fibril formation and elimination of neurotoxicity by a small molecule. Proc Natl Acad Sci U S A, 2004.
Luth, H.J., Holzer, M., Gartner, U., et al., Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer’s disease, in APP23 transgenic mice and after experimental brain lesion in rat: evidence for an induction by amyloid pathology. Brain Res, 2001. 913(1):57–67.
Su, J.H., Deng, G., and Cotman, C.W., Neuronal DNA damage precedes tangle formation and is associated with up-regulation of nitrotyrosine in Alzheimer’s disease brain. Brain Res, 1997. 774(1–2):193–199.
Gu, Z., Kaul, M., Yan, B., et al., S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science, 2002. 297(5584): 1186–1190.
Yong, V.W., Power, C., Forsyth, P., and Edwards, D.R., Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci, 2001. 2(7):502–511.
Meda, L., Cassatella, M.A., Szendrei, G.I., et al., Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature, 1995. 374 (6523):647–650.
El Khoury, J., Hickman, S.E., Thomas, C.A., et al., Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature, 1996. 382(6593): 716–719.
Griffin, W.S., Stanley, L.C., Ling, C., et al., Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer’s disease. Proc Natl Acad Sci U S A, 1989. 86(19):7611–7615.
Rogers, J., Schultz, J., Brachova, L., et al., Complement activation and beta-amyloid-mediated neurotoxicity in Alzheimer’s disease. Res Immunol, 1992. 143(6):624–630.
Brown, G.C. and Bal-Price, A., Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol, 2003. 27(3): 325–355.
Colton, C.A., Snell, J., Chernyshev, O., and Gilbert, D.L., Induction of superoxide anion and nitric oxide production in cultured microglia. Ann N Y Acad Sci, 1994. 738:54–63.
Harman, D., A hypothesis on the pathogenesis of Alzheimer’s disease. Ann N Y Acad Sci, 1996. 786: 152–168.
Byrne, E., Does mitochondrial respiratory chain dysfunction have a role in common neurodegenerative disorders? J Clin Neurosci, 2002. 9(5): 497–501.
Keller, J.N., Guo, Q., Holtsberg, F.W., et al., Increased sensitivity to mitochondrial toxininduced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. J Neurosci, 1998. 18(12):4439–4450.
Kruman, II and Mattson, M.P., Pivotal role of mitochondrial calcium uptake in neural cell apoptosis and necrosis. J Neurochem, 1999. 72(2):529–540.
Cadenas, E. and Davies, K.J., Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med, 2000.29(3–4):222–230.
Parker, W.D., Jr., Parks, J., Filley, C.M., and Kleinschmidt-DeMasters, B.K., Electron transport chain defects in Alzheimer’s disease brain. Neurology, 1994. 44(6):1090–1096.
Swerdlow, R.H., Parks, J.K., Cassarino, D.S., et al., Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology, 1997. 49(4):918–925.
Corral-Debrinski, M., Horton, T., Lott, M.T., et al., Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet, 1992. 2(4):324–329.
Wallace, D.C., Lott, M.T., and Brown, M.D., Mitochondrial defects in neurodegenerative diseases and aging, in Mitochondria and Free radicals in Neurodegenerative Diseases, M.F. Beal, N. Howell and I. Bodis-Walker, Editors. 1997, Wiley-Liss: New York. 283–307.
Price, D.L., Tanzi, R.E., Borchelt, D.R., and Sisodia, S.S., Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet, 1998. 32: 461–493.
Bush, A.I., Metals and neuroscience. Curr Opin Chem Biol, 2000. 4(2):184–191.
Huang, X., Moir, R.D., Tanzi, R.E., et al., Redoxactive metals, oxidative stress, and Alzheimer’s disease pathology. Ann N Y Acad Sci, 2004. 1012: 153–163.
Huang, X., Cuajungco, M.P., Atwood, C.S., et al., Alzheimer’s disease, beta-amyloid protein and zinc. J Nutr, 2000. 130(5S Suppl): 1488S–1492S.
Atwood, C.S., Huang, X., Moir, R.D., et al.., Role of free radicals and metal ions in the pathogenesis of Alzheimer’s disease. Met Ions Biol Syst, 1999. 36:309–364.
Smith, M.A., Harris, P.L., Sayre, L.M., and Perry, G., Iron accumulation in Alzheimer’s disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A, 1997. 94(18):9866–9868.
Martins, R.N., Harper, C.G., Stokes, G.B., and Masters, C.L., Increased cerebral glucose-6-phosphate dehydrogenase activity in Alzheimer’s disease may reflect oxidative stress. J Neurochem, 1986. 46(4):1042–1045.
Sayre, L.M., Perry, G., Harris, P.L., et al., In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition metals. J Neurochem, 2000. 74(1):270–279.
Bush, A.I., Masters, C.L., and Tanzi, R., E., Copper, beta-amyloid, and Alzheimer’s disease: tapping a sensitive connection. Proc Natl Acad Sci U S A, 2003. 100(20):11193–11194.
Atwood, C.S., Moir, R.D., Huang, X., et al., Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem, 1998. 273(21):12817–12826.
Atwood, C.S., Huang, X., Khatri, A., et al., Copper catalyzed oxidation of Alzheimer Aβ. Cell Mol Biol, 2000. 46(4):777–783.
Huang, X., Atwood, C.S., Hartshorn, M.A., et al., The Aβ peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry, 1999. 38(24):7609–7616.
Huang, X., Cuajungco, M.P., Atwood, C.S., et al., Cu(II) potentiation of Alzheimer Aβ neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem, 1999. 274(52):37111–37116.
Opazo, C., Huang, X., Cherny, R.A., et al., Metalloenzyme-like activity of Alzheimer’s disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2). J Biol Chem, 2002. 277(43):40302–40308.
Behl, C., Davis, J.B., Lesley, R., and Schubert, D., Hydrogen peroxide mediates amyloid beta protein toxicity. Cell, 1994. 77(6):817–827.
Morita, A., Kimura, M., and Itokawa, Y., The effect of aging on the mineral status of female mice. Biol Trace Elem Res, 1994. 42(2):165–177.
Takahashi, S., Takahashi, I., Sato, H., et al., Agerelated changes in the concentrations of major and trace elements in the brain of rats and mice. Biol Trace Elem Res, 2001. 80(2):145–158.
Lovell, M.A., Robertson, J.D., Teesdale, W.J., et al., Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci, 1998. 158(1):47–52.
Lee, J.Y., Cole, T.B., Palmiter, R.D., et al., Contribution by synaptic zinc to the genderdisparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci U S A, 2002. 99(11):7705–7710.
Yoshiike, Y., Tanemura, K., Murayama, O., et al., New insights on how metals disrupt amyloid betaaggregation and their effects on amyloid-beta cytotoxicity. J Biol Chem, 2001. 276(34):32293–32299.
Huang, X., Atwood, C.S., Moir, R.D., et al., Zincinduced Alzheimer’s Abeta1-40 aggregation is mediated by conformational factors. J Biol Chem, 1997. 272(42):26464–26470.
Terry, R.D., The pathogenesis of Alzheimer’s disease: an alternative to the amyloid hypothesis. J Neuropathol Exp Neurol, 1996. 55(10):1023–1025.
Atwood, C.S., Obrenovich, M.E., Liu, T., et al., Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev, 2003. 43(1):1–16.
Multhaup, G., Hesse, L., Borchardt, T., et al., Autoxidation of amyloid precursor protein and formation of reactive oxygen species. Adv Exp Med Biol, 1999. 448:183–192.
Butterfield, D.A., Drake, J., Pocernich, C., and Castegna, A., Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med, 2001. 7(12):548–554.
Arispe, N., Rojas, E., and Pollard, H.B., Alzheimer’s disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci U S A, 1993. 90(2):567–571.
Mattson, M.P., Tomaselli, K.J., and Rydel, R.E., Calcium-destabilizing and neurodegenerative effects of aggregated beta-amyloid peptide are attenuated by basic FGF. Brain Res, 1993. 621(1): 35–49.
Curtain, C.C., Ali, F.E., Smith, D.G., et al., Metal ions, pH, and cholesterol regulate the interactions of Alzheimer’s disease amyloid-beta peptide with membrane lipid. J Biol Chem, 2003. 278(5):2977–2982.
Cherny, R.A., Legg, J.T., McLean, C.A., et al., Aqueous dissolution of Alzheimer’s disease Aβ amyloid deposits by biometal depletion. J Biol Chem, 1999. 274(33):23223–23228.
Lau, T.L., Barnham, K.J., Curtain, C.C., et al., Magnetic resonance studies of β-amyloid peptides. Aust J Chem, 2003. 56:349–356.
Barnham, K.J., Ciccotosto, G.D., Tickler, A.K., et al., Neurotoxic, redox-competent Alzheimer’s beta-amyloid is released from lipid membrane by methionine oxidation. J Biol Chem, 2003. 278(44): 42959–42965.
Atwood, C.S., Scarpa, R.C., Huang, X., et al., Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem, 2000. 75(3):1219–1233.
Naslund, J., Schierhorn, A., Hellman, U., et al., Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer’s disease and normal aging. Proc Natl Acad Sci U S A, 1994. 91(18): 8378–8382.
Kuo, Y.M., Kokjohn, T.A., Beach, T.G., et al., Comparative analysis of amyloid-beta chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer’s disease brains. J Biol Chem, 2001. 276(16):12991–12998.
Palmblad, M., Westlind-Danielsson, A., and Bergquist, J., Oxidation of methionine 35 attenuates formation of amyloid beta-peptide 1-40 oligomers. J Biol Chem, 2002. 277(22):19506–19510.
Hou, L., Kang, I., Marchant, R.E., and Zagorski, M.G., Methionine 35 oxidation reduces fibril assembly of the amyloid abeta-(1-42) peptide of Alzheimer’s disease. J Biol Chem, 2002. 277(43): 40173–40176.
Dong, J., Atwood, C.S., Anderson, V.E., et al., Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. Biochemistry, 2003. 42(10):2768–2773.
Selkoe, D.J., The early diagnosis of Alzheimer’s disease., in The Pathophysiology of Alzheimer’s Disease. L.F.M. Scinto and K.R. Daffner, Editors. 2000, Humana: Totowa, NJ. 83–104.
Barrow, C.J., Advances in the development of Abeta-related therapeutic strategies for Alzheimer’s disease. Drug News Perspect, 2002. 15(2):102–109.
Auld, D.S., Kornecook, T.J., Bastianetto, S., and Quirion, R., Alzheimer’s disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol, 2002. 68(3):209–245.
Bowen, D.M., Palmer, A.M., Frances, P.T., et al., Classical neurotransmitters in Alzheimer’s disease, in Aging and the Brain. R.D. Terry, Editor. 1988, Raven Press: New York. 115–128.
Emilien, G., Beyreuther, K., Masters, C.L., and Maloteaux, J.M., Prospects for pharmacological intervention in Alzheimer’s disease. Arch Neurol, 2000. 57(4):454–459.
Mobius, H.J., Memantine: update on the current evidence. Int J Geriatr Psychiatry, 2003. 18(Suppl 1):S47–54.
Winblad, B. and Jelic, V., Treating the full spectrum of dementia with memantine. Int J Geriatr Psychiatry, 2003. 18(Suppl 1):S41–46.
Rogawski, M.A. and Wenk, G.L., The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev, 2003. 9:275–308.
Reisberg, B., Doody, R., Stoffler, A., et al., Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med, 2003. 348(14):1333–1341.
Moosmann, B. and Behl, C., Antioxidants as treatment for neurodegenerative disorders. Expert Opin Investig Drugs, 2002. 11(10):1407–1435.
Sano, M., Ernesto, C., Thomas, R.G., et al., A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med, 1997. 336(17):1216–1222.
Bano, S. and Parihar, M.S., Reduction of lipid peroxidation in different brain regions by a combination of alpha-tocopherol and ascorbic acid. J Neural Transm, 1997. 104(11-12):1277–1286.
Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. The Parkinson Study Group. N Engl J Med, 1993. 328(3):176–183.
Spina, M.B., Squinto, S.P., Miller, J., et al., Brainderived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and N-methyl-4-phenylpyridinium ion toxicity: involvement of the glutathione system. J Neurochem, 1992. 59(1):99–106.
Parihar, M.S. and Hemnani, T., Experimental excitotoxicity provokes oxidative damage in mice brain and attenuation by extract of Asparagus racemosus. J Neural Transm, 2004. 111(1):1–12.
Parihar, M.S. and Hemnani, T., Phenolic antioxidants attenuate hippocampal neuronal cell damage against kainic acid induced excitotoxicity. J Biosci, 2003. 28(1):121–128.
Beyer, R.E., An analysis of the role of coenzyme Q in free radical generation and as an antioxidant. Biochem Cell Biol, 1992. 70(6):390–403.
Hemmer, W. and Wallimann, T., Functional aspects of creatine kinase in brain. Dev Neurosci, 1993. 15(3–5):249–260.
Mendoza-Ramirez, J.L., Beltran-Parrazal, L., Verdugo-Diaz, L., et al., Delay in manifestations of aging by grafting NGF cultured chromaffin cells in adulthood. Neurobiol Aging, 1995. 16(6):907–916.
Behl, C. and Holsboer, F., The female sex hormone oestrogen as a neuroprotectant. Trends Pharmacol Sci, 1999. 20(11):441–444.
Xu, H., Gouras, G.K., Greenfield, J.P., et al., Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med, 1998. 4(4): 447–451.
LeVine III, H., Challenges of targeting Aβ fibrillogenesis and other protein folding disorders. Amyloid, 2003. 10:133–135.
Conway, K.A., Baxter, E.W., Felsenstein, K.M., and Reitz, A.B., Emerging beta-amyloid therapies for the treatment of Alzheimer’s disease. Curr Pharm Des, 2003. 9(6):427–447.
Xia, W., Amyloid inhibitors and Alzheimer’s disease. Curr Opin Investig Drugs, 2003. 4(1):55–59.
Lahiri, D.K., Farlow, M.R., Sambamurti, K., et al., A critical analysis of new molecular targets and strategies for drug developments in Alzheimer’s disease. Curr Drug Targets, 2003. 4(2):97–112.
Doraiswamy, P.M., Non-cholinergic strategies for treating and preventing Alzheimer’s disease. CNS Drugs, 2002. 16(12):811–824.
Maiorini, A.F., Gaunt, M.J., Jacobsen, T.M., et al., Potential novel targets for Alzheimer pharmacotherapy: I. Secretases. J Clin Pharm Ther, 2002. 27(3):169–183.
Jhee, S., Shiovitz, T., Crawford, A.W., and Cutler, N.R., Beta-amyloid therapies in Alzheimer’s disease. Expert Opin Investig Drugs, 2001. 10(4): 593–605.
Cutler, N.R. and Sramek, J.J., Review of the next generation of Alzheimer’s disease therapeutics: challenges for drug development. Prog Neuropsychopharmacol Biol Psychiatry, 2001. 25(1): 27–57.
Haass, C. and De Strooper, B., The presenilins in Alzheimer’s disease-proteolysis holds the key. Science, 1999. 286(5441):916–919.
Wong, G.T., Manfra, D., Poulet, F.M., et al., Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem, 2004. 279(13): 12876–12882.
King, G.D., Cherian, K., and Turner, R.S., X11alpha impairs gamma-but not beta-cleavage of amyloid precursor protein. J Neurochem, 2004. 88(4):971–982.
Lanz, T.A., Hosley, J.D., Adams, W.J., and Merchant, K.M., Studies of Abeta pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575). J Pharmacol Exp Ther, 2004. 309(1):49–55.
Kornilova, A.Y., Das, C., and Wolfe, M.S., Differential effects of inhibitors on the gamma-secretase complex. Mechanistic implications. J Biol Chem, 2003. 278(19):16470–16473.
Lanz, T.A., Himes, C.S., Pallante, G., et al., The gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces A beta levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther, 2003. 305(3):864–871.
Takahashi, Y., Hayashi, I., Tominari, Y., et al.., Sulindac sulfide is a noncompetitive gammasecretase inhibitor that preferentially reduces Abeta 42 generation. J Biol Chem, 2003. 278(20):18664–18670.
Wolfe, M.S., Therapeutic strategies for Alzheimer’s disease. Nat Rev Drug Discov, 2002. 1(11):859–866.
Schenk, D., Amyloid-beta immunotherapy for Alzheimer’s disease: the end of the beginning. Nat Rev Neurosci, 2002. 3(10):824–828.
McLaurin, J., Cecal, R., Kierstead, M.E., et al., Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis. Nat Med, 2002. 8(11):1263–1269.
Hock, C., Konietzko, U., Papassotiropoulos, A., et al., Generation of antibodies specific for betaamyloid by vaccination of patients with Alzheimer’s disease. Nat Med, 2002. 8(11):1270–1275.
Schenk, D., Barbour, R., Dunn, W., et al., Immunization with amyloid-β attenuates Alzheimerdisease-like pathology in the PDAPP mouse. Nature, 1999. 400(6740):173–177.
Janus, C., Vaccines for Alzheimer’s disease: how close are we? CNS Drugs, 2003. 17(7):457–474.
Cherny, R.A., Atwood, C.S., Xilinas, M.E., et al., Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron, 2001. 30(3):665–676.
Weiner, H.L., Lemere, C.A., Maron, R., et al., Nasal administration of amyloid-β peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol, 2000. 48(4):567–579.
Janus, C., Pearson, J., McLaurin, J., et al., Aβ-peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature, 2000. 408(6815):979–982.
Bard, F., Cannon, C., Barbour, R., et al., Peripherally administered antibodies against amyloid β peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer’s disease. Nat Med, 2000. 6(8):916–919.
DeMattos, R.B., Bales, K.R., Cummins, D.J., et al., Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A, 2001. 98(15):8850–8855.
Wilcock, D.M., DiCarlo, G., Henderson, D., et al., Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci, 2003. 23(9):3745–3751.
Robinson, S.R., Bishop, G.M., Lee, H.G., and Munch, G., Lessons from the AN 1792 Alzheimer vaccine: lest we forget. Neurobiol Aging, 2004. 25(5):609–615.
Broytman, O. and Malter, J.S., Anti-Abeta: The good, the bad, and the unforeseen. J Neurosci Res, 2004. 75(3):301–306.
Robinson, S.R., Bishop, G.M., and Munch, G., Alzheimer vaccine: amyloid-beta on trial. Bioessays, 2003. 25(3):283–288.
Munch, G. and Robinson, S.R., Potential neurotoxic inflammatory responses to Abeta vaccination in humans. J Neural Transm, 2002. 109(7–8):1081–1087.
Rogers, J., Webster, S., Lue, L.F., et al., Inflammation and Alzheimer’s disease pathogenesis. Neurobiol Aging, 1996. 17(5):681–686.
Weggen, S., Eriksen, J.L., Das, P., et al., A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature, 2001. 414(6860):212–216.
Beher, D., Clarke, E.E., Wrigley, J.D., et al., Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site-evidence for an allosteric mechanism. J Biol Chem, 2004.
Lim, G.P., Yang, F., Chu, T., et al., Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol Aging, 2001. 22(6):983–991.
Jantzen, P.T., Connor, K.E., DiCarlo, G., et al., Microglial activation and beta-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J Neurosci, 2002. 22(6):2246–2254.
Refolo, L.M., Pappolla, M.A., LaFrancois, J., et al., A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol Dis, 2001. 8(5):890–899.
Wolozin, B., Kellman, W., Ruosseau, P., et al., Decreased prevalence of Alzheimer’s disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol, 2000. 57(10): 1439–1443.
Jick, H., Zornberg, G.L., Jick, S.S., et al., Statins and the risk of dementia. Lancet, 2000. 356(9242): 1627–1631.
Sparks, D.L., Kuo, Y.M., Roher, A., et al., Alterations of Alzheimer’s disease in the cholesterol-fed rabbit, including vascular inflammation. Preliminary observations. Ann N Y Acad Sci, 2000. 903:335–344.
Refolo, L.M., Malester, B., LaFrancois, J., et al., Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis, 2000. 7(4):321–331.
Fassbender, K., Simons, M., Bergmann, C., et al., Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A, 2001. 98(10):5856–5861.
Wahrle, S., Das, P., Nyborg, A.C., et al., Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol Dis, 2002. 9(1):11–23.
Bush, A.I., Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol Aging, 2002. 23(6):1031–1038.
Padmanabhan, G., Klauss, E., and Florey, E.E., Clioquinol, in Analytical Profiles of Drug Substances. K. Florey, Editor. 1989, Academic Press: Orlando, FL. 57–90.
Ritchie, C.W., Bush, A.I., Mackinnon, A., et al., Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer’s disease: a pilot phase 2 clinical trial. Arch Neurol, 2003. 60(12):1685–1691.
Sair, H.I., Doraiswamy, P.M., and Petrella, J.R., In vivo amyloid imaging in Alzheimer’s disease. Neuroradiology, 2004. 46(2):93–104.
Zhang, J., Yarowsky, P., Gordon, M.N., et al., Detection of amyloid plaques in mouse models of Alzheimer’s disease by magnetic resonance imaging. Magn Reson Med, 2004. 51(3):452–457.
Benveniste, H., Einstein, G., Kim, K.R., et al., Detection of neuritic plaques in Alzheimer’s disease by magnetic resonance microscopy. Proc Natl Acad Sci U S A, 1999. 96(24):14079–14084.
Rapoport, S.I., Hydrogen magnetic resonance spectroscopy in Alzheimer’s disease. Lancet Neurol, 2002. 1(2):82.
Schuff, N., Capizzano, A.A., Du, A.T., et al., Selective reduction of N-acetylaspartate in medial temporal and parietal lobes in AD. Neurology, 2002. 58(6):928–935.
Petrella, J.R., Coleman, R.E., and Doraiswamy, P.M., Neuroimaging and early diagnosis of Alzheimer’s disease: a look to the future. Radiology, 2003. 226(2):315–336.
Phelps, M.E., PET: the merging of biology and imaging into molecular imaging. J Nucl Med, 2000. 41(4):661–681.
Devanand, D.P., Jacobs, D.M., Tang, M.X., et al., The course of psychopathologic features in mild to moderate Alzheimer’s disease. Arch Gen Psychiatry, 1997. 54(3):257–263.
Salmon, E., Sadzot, B., Maquet, P., et al. Differential diagnosis of Alzheimer’s disease with PET. J Nucl Med, 1994. 35(3):391–398.
Silverman, D.H., Cummings, J.L., Small, G., et al., Added clinical benefit of incorporating 2-deoxy-2-[18F]fluoro-D-glucose with positron emission tomography into the clinical evaluation of patients with cognitive impairment. Mol Imaging Biol, 2002. 4(4):283–2893.
Kennedy, A.M., Frackowiak, R.S., Newman, S.K., et al., Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer’s disease. Neurosci Lett, 1995. 186(1):17–20.
Small, G.W., Mazziotta, J.C., Collins, M.T., et al., Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer’s disease. JAMA, 1995. 273(12):942–947.
Silverman, D.H., Small, G.W., Chang, C.Y., et al., Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA, 2001. 286(17):2120–2127.
Zhuang, Z.P., Kung, M.P., Wilson, A., et al., Structure-activity relationship of imidazo[1,2-a]pyridines as ligands for detecting beta-amyloid plaques in the brain. J Med Chem, 2003. 46(2):237–243.
Kung, M.P., Hou, C., Zhuang, Z.P., et al., IMPY: an improved thioflavin-T derivative for in vivo labeling of beta-amyloid plaques. Brain Res Bull, 2002. 956(2):202–210.
Ono, M., Kung, M.P., Hou, C., and Kung, H.F., Benzofuran derivatives as Abeta-aggregate-specific imaging agents for Alzheimer’s disease. Nucl Med Biol, 2002. 29(6):633–642.
Ono, M., Wilson, A., Nobrega, J., et al., 11Clabeled stilbene derivatives as Abeta-aggregate-specific PET imaging agents for Alzheimer’s disease. Nucl Med Biol, 2003. 30(6):565–571.
Kung, M.P., Skovronsky, D.M., Hou, C., et al., Detection of amyloid plaques by radioligands for Abeta40 and Abeta42: potential imaging agents in Alzheimer’s patients. J Mol Neurosci, 2003. 20(1): 15–24.
Kung, M.P., Zhuang, Z.P., Hou, C., et al., Characterization of radioiodinated ligand binding to amyloid beta plaques. J Mol Neurosci, 2003. 20(3): 249–254.
Lee, C.W., Kung, M.P., Hou, C., and Kung, H.F., Dimethylamino-fluorenes: ligands for detecting beta-amyloid plaques in the brain. Nucl Med Biol, 2003. 30(6):573–580.
Link, C.D., Johnson, C.J., Fonte, V., et al., Visualization of fibrillar amyloid deposits in living, transgenic Caenorhabditis elegans animals using the sensitive amyloid dye, X-34. Neurobiol Aging, 2001. 22(2):217–226.
Klunk, W.E., Debnath, M.L., and Pettegrew, J.W., Development of small molecule probes for the betaamyloid protein of Alzheimer’s disease. Neurobiol Aging, 1994. 15(6):691–698.
Bacskai, B.J., Klunk, W.E., Mathis, C.A., and Hyman, B.T., Imaging amyloid-beta deposits in vivo. J Cereb Blood Flow Metab, 2002. 22(9): 1035–1041.
Klunk, W.E., Bacskai, B.J., Mathis, C.A., et al., Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative. J Neuropath Exp Neurol, 2002. 61(9):797–805.
Kung, M.P., Hou, C., Zhuang, Z.P., et al., Radioiodinated styrylbenzene derivatives as potential SPECT imaging agents for amyloid plaque detection in Alzheimer’s disease. J Mol Neurosci, 2002. 19(1–2):7–10.
Zhuang, Z.P., Kung, M.P., Hou, C., et al., IBOX(2-(4-dimethylaminophenyl)-6-iodobenzoxazole): a ligand for imaging amyloid plaques in the brain. Nucl Med Biol, 2001. 28(8):887–894.
Lee, C.W., Zhuang, Z.P., Kung, M.P., et al., Isomerization of (Z,Z) to (E,E)1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene in strong base: probes for amyloid plaques in the brain. J Med Chem., 2001. 44(14):2270–2275.
Klunk, W.E., Wang, Y., Huang, G.F., et al., The binding of 2-(4-methylaminophenyl)benzothiazole to postmortem brain homogenates is dominated by the amyloid component. J Neurosci, 2003. 23(6): 2086–2092.
Klunk, W.E., Wang, Y., Huang, G.F., et al., Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sci, 2001. 69(13):1471–1484.
Bacskai, B.J., Hickey, G.A., Skoch, J., et al., Fourdimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A, 2003. 100(21):12462–12467.
Mathis, C.A., Bacskai, B.J., Kajdasz, S.T., et al., A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem Lett, 2002. 12(3):295–298.
Mathis, C.A., Holt, D.P., Wang, Y., et al., Lipophilic 11C-labelled thioflavin-T analogues for imaging amyloid plaques in Alzheimer’s disease. J Label Compd Radiopharm, 2001. 44(Suppl 1):S26–S28.
Mathis, C.A., Wang, Y., Holt, D.P., et al., Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem, 2003. 46(13):2740–2754.
Wang, Y., Klunk, W.E., Huang, G.F., et al., Synthesis and evaluation of 2-(3-iodo-4-aminophenyl)-6-hydroxybenzothiazole for in vivo quantitation of amyloid deposits in Alzheimer’s disease. J Mol Neurosci, 2002. 19(1–2):11–16.
Wang, Y., Mathis, C.A., Huang, G.F., et al.., Effects of lipophilicity on the affinity and nonspecific binding of iodinated benzothiazole derivatives. J Mol Neurosci, 2003. 20(3):255–260.
Helmuth, L., Long-awaited technique spots Alzheimer’s toxin. Science, 2002. 297:752–753.
Klunk, W.E., Engler, H., Nordberg, A., et al., Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol, 2004. 55: 306–319.
Zhuang, Z.P., Kung, M.P., Hou, C., et al., Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates. J Med Chem, 2001. 44(12):1905–1914.
Skovronsky, D.M., Zhang, B., Kung, M.P., et al., In vivo detection of amyloid plaques in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A, 2000. 97(13):7609–7614.
Kung, H.F., Lee, C.W., Zhuang, Z.P., et al. Novel stilbenes as probes for amyloid plaques. J Am Chem Soc, 2001. 123(50):12740–12741.
Schmidt, M.L., Schuck, T., Sheridan, S., et al., The fluorescent Congo red derivative, (trans, trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB), labels diverse β-pleated sheet structures in postmortem human neurodegenerative disease brains. Am J Pathol, 2001. 159(3):937–943.
Shimadzu, H., Suemoto, T., Suzuki, M., et al., A novel probe for imaging amyloid-b: Synthesis of F-18 labelled BF-108, an Acridine Orange analog. J Label Compd Radiopharm, 2003. 46:765–772.
Agdeppa, E.D., Kepe, V., Petri, A., et al., In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile. Neuroscience, 2003. 117(3):723–730.
Agdeppa, E.D., Kepe, V., Liu, J., et al., Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for β-amyloid plaques in Alzheimer’s disease. J Neurosci, 2001. 21(24):RC189.
Barrio, J.R., Huang, S.C., Cole, G., et al., PET imaging of tangles and plaques in Alzheimer’s disease with a highly lipophilic probe. J Label Compd Radiopharm, 1999. 42:S194–S195.
Shoghi-Jadid, K., Small, G.W., Agdeppa, E.D., et al., Localisation of neurofibrillary tangles and βamyloid plaques in the brains of living patients with Alzheimer’s disease. Am J Ger Psychiatry, 2002. 10(1):24–35.
Bresjanac, M., Smid, L.M., Vovko, T.D., et al., Molecular-imaging probe 2-(1-[6-[(2-fluoroethyl) (methyl) amino]-2-naphthyl]ethylidene) malononitrile labels prion plaques in vitro. J Neurosci, 2003. 23(22):8029–8033.
Agdeppa, E.D., Kepe, V., Shoghi-Jadid, K., et al., In vivo and in vitro labeling of plaques and tangles in the brain of an Alzheimer’s disease patient: a case study. J Nucl Med, 2001. 42(Suppl 1): 65P.
Small, G.W., Agdeppa, E.D., Kepe, V., et al., In vivo brain imaging of tangle burden in humans. J Mol Neurosci, 2002. 19(3):323–327.
Lee, V.M., Related Amyloid binding ligands as Alzheimer’s disease therapies. Neurobiol Aging, 2002. 23(6):1039–1042.
Marshall, J.R., Stimson, E.R., Ghilardi, J.R., et al., Noninvasive imaging of peripherally injected Alzheimer’s disease type synthetic A beta amyloid in vivo. Bioconjug Chem, 2002. 13(2):276–284.
Maggio, J.E., Stimson, E.R., Ghilardi, J.R., et al., Reversible in vitro growth of Alzheimer’s disease beta-amyloid plaques by deposition of labeled amyloid protein. Proc Natl Acad Sci U S A, 1992. 89(12):5462–5466.
Friedland, R.P., Shi. J, Lamanna, J.C., et al., Prospects for noninvasive imaging of brain amyloid beta in Alzheimer’s disease. Ann N Y Acad Sci, 2000. 903:123–128.
Ghilardi, J.R., Catton, M., Stimson, E.R., et al., Intra-arterial infusion of [125I]A beta 1-40 labels amyloid deposits in the aged primate brain in vivo. Neuroreport, 1996. 7(15–17):2607–2611.
Kurihara, A. and Pardridge, W.M., Abeta(1-40) peptide radiopharmaceuticals for brain amyloid imaging: (111)In chelation, conjugation to poly(ethylene glycol)-biotin linkers, and autoradiography with Alzheimer’s disease brain sections. Bioconjug Chem, 2000. 11(3):380–386.
Saito, Y., Buciak, J., Yang, J., and Pardridge, W.M., Vector-mediated delivery of 125I-labeled betaamyloid peptide A beta 1-40 through the bloodbrain barrier and binding to Alzheimer’s disease amyloid of the A beta 1-40/vector complex. Proc Natl Acad Sci U S A, 1995. 92(22):10227–10231.
Majocha, R.E., Reno, J.M., Friedland, R.P., et al., Development of a monoclonal antibody specific for β/A4 amyloid in Alzheimer’s disease brain for application to in vivo imaging of amyloid angiopathy. J Nucl Med, 1992. 33(12):2184–2189.
Walker, L.C., Price, D.L., Voytko, M.L., and Schenk, D.B., Labelling of cerebral amyloid in vivo with a monoclonal antibody. J Neuropathol Exp Neurol, 1994. 53(4):377–383.
Shi, J., Perry, G., Berridge, M.S., et al., Labeling of cerebral amyloid beta deposits in vivo using intranasal basic fibroblast growth factor and serum amyloid P component in mice. J Nucl Med, 2002. 43(8):1044–1051.
Knopman, D.S., DeKosky, S.T., Cummings, J.L., et al., Practice parameter: Diagnosis of dementia (an evidence based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 2001. 56(9):1143–1153.
Doody, R.S., Stevens, J.C., Beck, C., et al., Practice parameter: management of dementia (an evidencebased review)-report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 2001. 56(9):1154–1166.
Petersen, R.C., Stevens, J.C., Ganguli, M., et al., Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review)-report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 2001. 56(9):1133–1142.
Silverman, D.H., Chang, C.Y., Cummings, J.L., et al., Prognostic value of regional brain metabolism in evaluation of dementia. J Nucl Med, 1999. 40(Suppl 1): 71P.
Chang, C.Y. and Silverman, D.H., Accuracy of early diagnosis and its impact on the management and course of Alzheimer’s disease. Expert Rev Mol Diagn, 2004. 4:63–69.
Silverman, D.H., Gambhir, S.S., Huang, H.W., et al., Evaluating early dementia with and without assessment of regional cerebral metabolism by PET: a comparison of predicted costs and benefits. J Nucl Med, 2002. 43(2):253–266.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Springer-Verlag London Limited
About this chapter
Cite this chapter
Villemagne, V.L. et al. (2007). The Aβcentric Pathway of Alzheimer’s Disease. In: Barrow, C.J., Small, D.H. (eds) Abeta Peptide and Alzheimer’s Disease. Springer, London. https://doi.org/10.1007/978-1-84628-440-3_2
Download citation
DOI: https://doi.org/10.1007/978-1-84628-440-3_2
Publisher Name: Springer, London
Print ISBN: 978-1-85233-961-6
Online ISBN: 978-1-84628-440-3
eBook Packages: MedicineMedicine (R0)