Advertisement

Mechanisms of synaptic pathology in Alzheimer’s disease

  • E. Masliah
Part of the Journal of Neural Transmission. Supplementa book series (NEURAL SUPPL, volume 53)

Summary

Neurodegenerative disorders are characterized by damage to selective neuronal populations that could be followed or preceded by synaptic injury. Therefore, specific mutations in and other alterations of synaptic proteins might lead to particular neurodegenerative diseases. The predominant hypothesis is that these mutations result in an increased production of amyloid β-protein 1–42 which acts as a neurotoxin. However, it could also be postulated that amyloid precursor protein might play an important role in synaptic function and neuronal maintenance, and that its abnormal activity may lead to neurodegeneration. Recent studies have shown that amyloid precursor protein has an important role in regulating glutamate levels at the synaptic site by modulating the activity of glutamate transporters. The objectives of this manuscript are to highlight recent data supporting the hypothesis that neurodegeneration in Alzheimer’s disease might be the combined result of abnormal protective activity of amyloid precursor protein and amyloid β-protein toxicity.

Keywords

Alzheimer Disease Amyloid Precursor Protein Entorhinal Cortex Glutamate Transporter Amyloid Precursor Protein Processing 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Arai H, Lee VM-Y, Messinger ML, Greenberg BD, Lowery DE, Trojanowski JQ (1991) Expression patterns of β-amyloid precursor protein (β-APP) in neural and nenneural tissues from Alzheimer’s disease and control subjects. Ann Neurol 30: 686–693PubMedCrossRefGoogle Scholar
  2. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992a) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42: 631–639PubMedCrossRefGoogle Scholar
  3. Arriagada PV, Marzloff K, Hyman BT (1992b) Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42: 1681–1688PubMedCrossRefGoogle Scholar
  4. Beach TG, Walker R, McGeer EG (1989) Patterns of gliosis in Alzheimer’s disease and aging cerebrum. Glia 2: 420–436PubMedCrossRefGoogle Scholar
  5. Behl C, Davis J, Lesley R, Schubert D (1994) Hydrogen peroxide mediates amyloid β protein toxicity. Cell 77: 817–827PubMedCrossRefGoogle Scholar
  6. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aβ 1-42/1-40 ratio in vitro and in vivo. Neuron 17: 1005–1013PubMedCrossRefGoogle Scholar
  7. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82: 239–259PubMedCrossRefGoogle Scholar
  8. Butterfield DA, Hensley K, Harris M, Mattson MP, Carney J (1994) β-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer’s disease. Biochem Biophys Res Commun 200: 710–715PubMedCrossRefGoogle Scholar
  9. Casado M, Bendahan A, Zafra F, Danbolt NC, Aragon C, Gimenez C, Kanner BI (1993) Phosphorylation and modulation of brain glutamate transporters by protein kinase C. J Biol Chem 268: 27313–27317PubMedGoogle Scholar
  10. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Liberburg I, Selkoe DJ (1992) Mutation in the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature 360: 672–674PubMedCrossRefGoogle Scholar
  11. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Subert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Hong Y, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St. George Hyslop P, Selkoe D (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nature Med 3: 67–72PubMedCrossRefGoogle Scholar
  12. Clark RF, Goate AM (1993) Molecular genetics of Alzheimer’s disease. Arch Neurol 50: 1164–1172PubMedCrossRefGoogle Scholar
  13. Cole GM, Masliah E, Huynh TV, DeTeresa R, Terry RD, Okudea C, Saitoh T (1989) An antiserum against amyloid β-protein precursor detects a unique peptide in Alzheimer brain. Neurosci Lett 100: 340–346PubMedCrossRefGoogle Scholar
  14. Collaborative Group (1995) The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Alzheimer’s Disease Collaborative Group. Nature Genet 11: 219–222Google Scholar
  15. Cowburn R, Hardy J, Roberts P, Briggs R (1988) Presynaptic and postsynaptic glutamatergic function in Alzheimer’s disease. Neurosci Lett 86: 109–113PubMedCrossRefGoogle Scholar
  16. Cowburn RF, Hardy JA, Roberts PJ (1990) Glutamatergic neurotransmission in Alzheimer’s disease. Biochem Soc Trans 18: 390–392PubMedGoogle Scholar
  17. Cras P, Kawai M, Lowery D, Gonzalez-DeWhitt P, Greenberg B, Perry G (1991) Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein. Proc Natl Acad Sci USA 88: 7552–7556PubMedCrossRefGoogle Scholar
  18. Cummings BJ, Cotman CW (1995) Image analysis of β-amyloid load in Alzheimer’s disease and relation to dementia severity. Lancet 346: 1524–1528PubMedCrossRefGoogle Scholar
  19. De Strooper B, Craessaerts K, Dewachter I, Moechars D, Greenberg B, Van Leuven F, Van Den Berghe H (1995) Missorting of amyloid precursor protein in MDCK cells. J Biol Chem 270: 4058–4065PubMedCrossRefGoogle Scholar
  20. DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27: 457–464CrossRefGoogle Scholar
  21. Dickson DW, Farlo J, Davies P, Crystal H, Fuld P, Yen SC (1988) Alzheimer disease. A double immunohistochemical study of senile plaques. Am J Pathol 132: 86–101Google Scholar
  22. Eccles JC (1981) The modular operation of the cerebral neocortex considered as the material basis of mental events. Neuroscience 6: 1839–1856PubMedCrossRefGoogle Scholar
  23. Eccles JC (1984) The cerebral neocortex: a theory of its operation. In: Jones EG, Peters A (eds) Cerebral cortex, vol 2. Functional properties of cortical cells. Plenum Press, New York, pp 1–38Google Scholar
  24. Furukawa K, Sopher BL, Rydel RE, Begley JG, Pham DG, Martin GM, Fox M, Mattson MP (1996) Increased activity regulating and neuroprotective efficacy of α-secretase-derived secreted amyloid precursor protein conferred by a c-terminal heparin-binding domain. J Neurochem 67: 1882–1892PubMedCrossRefGoogle Scholar
  25. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemes J, Donaldson T, Gillespie F, Guido T, Hagopian S, Johnson-Wood K, Khan K, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, McConlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373: 523–527PubMedCrossRefGoogle Scholar
  26. Games D, Masliah E, Lee M, Johnson-Wood K, Schenk D (1997) Neurodegenerative Alzheimer-like pathology in PDAPP 717V→F transgenic mice. In: Hyman BT, Duyckaerts C, Christen Y (eds) Connections, cognition and Alzheimer’s disease. Springer, Berlin Heidelberg New York Tokyo, pp 105–119CrossRefGoogle Scholar
  27. Goate A, Chartier-Harlin M-C, Mullan M, Brown J, Crawford F, Fidani L, Guiffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Williamson R, Rossor M, Owen M, Hardy J (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349: 704–706PubMedCrossRefGoogle Scholar
  28. Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255: 728–730PubMedCrossRefGoogle Scholar
  29. Gomez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16: 4491–4500PubMedGoogle Scholar
  30. Goodman Y, Mattson MP (1994) Secreted forms of β-amyloid precursor protein protect hippocampal neurons against amyloid β-peptide-induced oxidative injury. Exp Neurol 128: 1–12PubMedCrossRefGoogle Scholar
  31. Haass C, Koo E, Capell A, Teplow D, Selkoe DJ (1995) Polarized sorting of β-amyloid precursor protein and its proteolytic products in MDCK cells is regulated by two independent signals. J Cell Biol 128: 537–547PubMedCrossRefGoogle Scholar
  32. Harris ME, Wang Y, Pedigo NWJr, Hensley K, Buttefield DA, Carney JM (1996) Amyloid β peptide (25–35) inhibits Na+-dependent glutamate uptake in rat hippocampal astrocyte cultures. J Neurochem 67: 277–286PubMedCrossRefGoogle Scholar
  33. Heinonen O, Soininen H, Sorvari H, Kosunene O, Paljarvi L, Koivisto E, Riekkinen PJ (1995) Loss of synaptophysin-like immunoreactivity in the hippocampal formation is an early phenomenon in Alzheimer’s disease. Neuroscience 64: 375–384PubMedCrossRefGoogle Scholar
  34. Hof PR, Morrison JH (1991) Neocortical neuronal subpopulations labeled by a monoclonal antibody to calbindin exhibit differential vulnerability in Alzheimer’s disease. Exp Neurol 111: 293–301PubMedCrossRefGoogle Scholar
  35. Hof PR, Morrison JH (1994) The cellular basis of cortical disconnection in Alzheimer disease and related dementing conditions. In: Terry RD, Katzman R, Bick KL (eds) Alzheimer disease. Raven Press, New York, pp 197–230Google Scholar
  36. Hyman BT, Van Hoesen GW, Kromer LJ, Damasio AR (1986) Perforant pathway changes in the memory impairment of Alzheimer’s disease. Ann Neurol 20: 472–481PubMedCrossRefGoogle Scholar
  37. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara I (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species in A beta 42(43). Neuron 13: 45–53PubMedCrossRefGoogle Scholar
  38. Kovacs DM, Fausett HJ, Page KJ, Kim TW, Moir RD, Merriam DE, Hollister RD, Hallmark OG, Mancini R, Felsenstein KM (1996) Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nature Med 2: 224–229PubMedCrossRefGoogle Scholar
  39. Lassmann H, Weiler R, Fischer P, Bancher C, Jellinger K, Floor E, Danielczyk W, Seitelberger F, Winkler H (1992) Synaptic pathology in Alzheimer’s disease: immunological data for markers of synaptic and large dense-core vesicles. Neuroscience 46: 1–8PubMedCrossRefGoogle Scholar
  40. Liu X, Erikson C, Brun A (1996) Cortical synaptic changes and gliosis in normal aging, Alzheimer’s disease and frontal lobe degeneration. Dementia 7: 128–134PubMedGoogle Scholar
  41. Lo A, Haass C, Wagner S, Teplow D, Sisodia S (1994) Metabolism of the “Swedish” amyloid precursor protein variant in Madin-Darby canine kidney cells. J Biol Chem 269: 30966–30973PubMedGoogle Scholar
  42. Lorenzo A, Yankner BA (1994) β-Amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc Natl Acad Sci USA 91: 12243–12247PubMedCrossRefGoogle Scholar
  43. Mark RJ, Hensley K, Butterfield DA, Mattson MP (1995) Amyloid β-peptide impairs ionmotive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death. J Neurosci 15: 6239–6249PubMedGoogle Scholar
  44. Martin LJ, Cork LC, Koo EH, Sisodia SS, Weidemann A, Beyreuther K, Masters C, Price DL (1989) Localization of amyloid precursor protein (APP) in brains of young and aged monkeys. Soc Neurosci Abstr 15: 23Google Scholar
  45. Martin LJ, Pardo CA, Cork LC, Price DL (1994) Synaptic pathology and glial reponses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex. Am J Pathol 145: 1358–1381PubMedGoogle Scholar
  46. Masliah E (1995) Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol Histopathol 10: 509–519PubMedGoogle Scholar
  47. Masliah E, Terry R (1994) The role of synaptic pathology in the mechanisms of dementia in Alzheimer’s disease. Clin Neurosci 1: 192–198Google Scholar
  48. Masliah E, Mallory M, Hansen L, Alford M, Albright T, Terry R, Shapiro P, Sundsmo M, Saitoh T (1991) Immunoreactivity of CD45, a protein phosphotyrosine phosphatase, in Alzheimer disease. Acta Neuropathol 83: 12–20PubMedCrossRefGoogle Scholar
  49. Masliah E, Mallory M, Ge N, Saitoh T (1992a) Amyloid precursor protein is localized in growing neurites of neonatal rat brain. Brain Res 593: 323–328PubMedCrossRefGoogle Scholar
  50. Masliah E, Mallory M, Hansen L, Alford M, DeTeresa R, Terry R, Baudier J, Saitoh T (1992b) Localization of amyloid precursor protein in GAP43-immunoreactive aberrant sprouting neurites in Alzheimer’s disease. Brain Res 574: 312–316PubMedCrossRefGoogle Scholar
  51. Masliah E, Mallory M, Hansen L, Alford M, DeTeresa R, Terry R (1993) An antibody against phosphorylated neurofilaments identifies a subset of damaged association axons in Alzheimer’s disease. Am J Pathol 142: 871–882PubMedGoogle Scholar
  52. Masliah E, Mallory M, Hansen L, DeTeresa R, Alford M, Terry R (1994) Synaptic and neuritic alterations during the progression of Alzheimer’s disease. Neurosci Lett 174: 67–72PubMedCrossRefGoogle Scholar
  53. Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L (1996a) Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann Neurol 40: 759–766PubMedCrossRefGoogle Scholar
  54. Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D (1996b) Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F β-amyloid precursor protein and Alzheimer’s disease. J Neurosci 16: 5795–5811PubMedGoogle Scholar
  55. Masliah E, Westland CE, Abraham CR, Mallory M, Veinbergs I, Rockenstein EM, Mucke L (1997) Amyloid precursor protein protects neurons of transgenic mice against acute and chronic excitotoxic injuries in vivo. Neuroscience 78: 135–141PubMedCrossRefGoogle Scholar
  56. Masters CL, Multhaup G, Simms G, Pottglesser J, Martins RN, Beyreuther K (1985) Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer’s disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J 4: 2757–2763PubMedGoogle Scholar
  57. Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I, Rydel RE (1993a) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein. Neuron 10: 243–254PubMedCrossRefGoogle Scholar
  58. Mattson MP, Tomaselli KJ, Rydel RE (1993b) Calcium-destabilizing and neurodegenerative effects of aggregated β-amyloid peptide are attenuated by basic FGF. Brain Res 621: 35–49PubMedCrossRefGoogle Scholar
  59. Mucke L, Masliah E, Johnson WB, Ruppe MD, Rockenstein EM, Forss-Petter S, Pietropaolo M, Mallory M, Abraham CR (1994) Synaptotrophic effects of human amyloid β protein precursors in the cortex of transgenic mice. Brain Res 666: 151–167PubMedCrossRefGoogle Scholar
  60. Mucke L, Abraham CR, Ruppe MD, Rockenstein EM, Toggas SM, Alford M, Masliah E (1995) Protection against HIV-1 gp 120-induced brain damage by neuronal over-expression of human amyloid precursor protein (hAPP). J Exp Med 181: 1551–1556PubMedCrossRefGoogle Scholar
  61. Pericak-Vance MA, Bass MP, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA, Menold MM, Conneally PM, Small GW, Vance JM, Saunders AM, Roses AD, Haines JL (1997) Complete genomic screen in late-onset familial Alzheimer disease. JAMA 278: 1237–1241PubMedCrossRefGoogle Scholar
  62. Perry EK, Perry RH, Blessed G, Tomlinson BE (1977) Neurotransmitter enzyme abnormalities in senile dementia: CAT and GAD activities in necropsy tissue. J Neurol Sci 34: 247–265PubMedCrossRefGoogle Scholar
  63. Perry EK, McKeith I, Thompson P (1991) Topography, extent, and clinical relevance of neurochemical deficits in dementia of Lewy body type, Parkinson’s disease, and Alzheimer’s disease. Ann NY Acad Sci 640: 197–202PubMedGoogle Scholar
  64. Price DL, Sisodia SS, Gandy SE (1995) Amyloid β amyloidosis in Alzheimer’s disease. Curr Opin Neurol 8: 268–274PubMedCrossRefGoogle Scholar
  65. Rockenstein EM, McConlogue L, Tan H, Power M, Masliah E, Mucke L (1995) Levels and alternative splicing of amyloid β protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer’s disease. J Biol Chem 270: 28257–28267PubMedCrossRefGoogle Scholar
  66. Rogers J, Luber-Narod J, Styren SD, Civin WH (1988) Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 9: 339–349PubMedCrossRefGoogle Scholar
  67. Rothstein JD, Jin L, Dykes-Hoberg M, Kuncl RW (1993) Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc Natl Acad Sci USA 90: 6591–6595PubMedCrossRefGoogle Scholar
  68. Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate trasporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38: 73–84PubMedCrossRefGoogle Scholar
  69. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16: 675–686PubMedCrossRefGoogle Scholar
  70. Saitoh T, Kang D, Mallory M, DeTeresa R, Masliah E (1997) Glial cells in Alzheimer’s disease: preferential effect of APOE risk on scattered microglia. Gerontology 43: 109–118PubMedCrossRefGoogle Scholar
  71. Samuel W, Masliah E, Terry R (1994) Hippocampal connectivity and Alzheimer’s dementia: effects of pathology in a two-component model. Neurology 44: 2081–2088PubMedCrossRefGoogle Scholar
  72. Saunders AM, Strittmatter WJ, Schmechel D, St. George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD (1993) Association of apolipoprotein E allele E4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43: 1467–1472PubMedCrossRefGoogle Scholar
  73. Scott HL, Tannenberg AEG, Dodd PR (1995) Variant forms of neuronal glutamate trasporter sites in Alzheimer’s disease cerebral cortex. J Neurochem 64: 2193–2202PubMedCrossRefGoogle Scholar
  74. Selkoe DJ (1989) Amyloid β protein precursor and the pathogenesis of Alzheimer’s disease. Cell 58: 611–612PubMedCrossRefGoogle Scholar
  75. Selkoe DJ (1993) Physiological production of the β-amyloid protein and the mechanisms of Alzheimer’s disease. Trends Neurosci 16: 403–409PubMedCrossRefGoogle Scholar
  76. Selkoe D (1994a) Cell biology of the amyloid β-protein precursor and the mechanisms of Alzheimer’s disease. Annu Rev Cell Biol 10: 373–403PubMedCrossRefGoogle Scholar
  77. Selkoe DJ (1994b) Normal and abnormal biology of the β-amyloid precursor protein. Ann Rev Neurosci 17: 489–517PubMedCrossRefGoogle Scholar
  78. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C, McCormack R, Wolfert R, Selkoe D, Lieberburg I, Schenk D (1992) Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature 359: 325–327PubMedCrossRefGoogle Scholar
  79. Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai X-D, McKay DM, Tintner R, Frangione B, Younkin SG (1992) Production of the Alzheimer amyloid β protein by normal proteolytic processing. Science 258: 126–129PubMedCrossRefGoogle Scholar
  80. Sisodia SS, Price DL (1995) Role of the β-amyloid protein in Alzheimer’s disease. FASEB J 9: 366–370PubMedGoogle Scholar
  81. Sisodia SS, Koo EH, Beyreuther K, Unterbeck A, Price DL (1990) Evidence that β-amyloid protein in Alzheimer’s disease is not derived by normal processing. Science 248: 492–494PubMedCrossRefGoogle Scholar
  82. Terry RD, Wisniewski HM (1970) The ultrastructure of the neurofibrillary tangle and the senile plaque. In: Wolstenholme GEW, O’Connor M (eds) Ciba Foundation Symposium on Alzheimer’s disease and related conditions. Churchill, London, pp 145–168Google Scholar
  83. Terry RD, Peck A, DeTeresa R, Schechter R, Horoupian DS (1981) Some morphometric aspects of the brain in senile dementia of the Alzheimer type. Ann Neurol 10: 184–192PubMedCrossRefGoogle Scholar
  84. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30: 572–580PubMedCrossRefGoogle Scholar
  85. Terry RD, Hansen L, Masliah E (1994) Structural alterations in Alzheimer disease. In: Terry RD, Katzman R (eds) Alzheimer disease. Raven Press, New York, pp 179–196Google Scholar
  86. Voytko ML, Olton DS, Richardson RT, Gorman LK, Tobin JR, Price DL (1994) Basal forebrain lesions in monkeys disrupt attention but not learning and memory. J Neurosci 14: 167–186PubMedGoogle Scholar
  87. Weiss JH, Pike CJ, Cotman CW (1994) Ca2+ channel blockers attenuate β-amyloid peptide toxicity to cortical neurons in culture. J Neurochem 62: 372–375PubMedCrossRefGoogle Scholar
  88. Wragg M, Hutton M, Talbot C, Alzheimer’s Disease Collaborative Group (1996) Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer’s disease. Lancet 347: 509–512PubMedCrossRefGoogle Scholar
  89. Yamaguchi H, Hirai S, Morimatso M, Shoji M, Ihara Y (1988) A variety of cerebral amyloid deposits in the brains of Alzheimer-type dementia demonstrated by β-protein immunostaining. Acta Neuropathol 76: 541–549PubMedCrossRefGoogle Scholar
  90. Yankner BA (1996) Mechanisms of neuronal degeneration in Alzheimer’s disease. Neuron 16: 921–932PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1998

Authors and Affiliations

  • E. Masliah
    • 1
    • 2
  1. 1.Departments of Neurosciences and Pathology, School of MedicineUniversity of CaliforniaSan Diego, La JollaUSA
  2. 2.Departments of NeurosciencesUniversity of California San DiegoLa JollaUSA

Personalised recommendations