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Connections, Cognition and Alzheimer’s Disease pp 121–140Cite as

Molecular Mechanisms of Synaptic Disconnection in Alzheimer’s Disease

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Part of the book series: Research and Perspectives in Alzheimer’s Disease ((ALZHEIMER))

Abstract

Synaptic loss and neurofibrillary pathology are major contributors to the cognitive deficits in Alzheimer’s disease (AD), indicating an altered connectivity of association neurocircuitries. Synaptic damage occurs early in the development of AD, suggesting that synapse pathology is a primary rather than a secondary event. The mechanisms of synaptic damage and neurodegeneration in AD are not completely understood. Recent studies have suggested that abnormal expression and/or processing of growth-associated proteins in the central nervous system might play a role in the mechanisms leading to synaptic damage and neurodegeneration in AD. Prominent among these proteins are amyloid precursor protein (APP), apolipoprotein E (apoE), and non Aβ amyloid component (NAC) precursor (NACP). All of these molecules have several common features: 1) modulation of synaptic function, 2) involvement in amyloidogenesis, and 3) mutations (APP) and polymorphisms (APOE, NACP) that are associated with a higher risk for AD. Abnormal functioning of synaptic-related proteins with amyloidogenic potential might play a central role in the pathogenesis of AD. In this context, the main objectives of this manuscript are to review the contribution of synaptic alterations to the mechanisms of dementia in AD and to discuss some of the possible mechanisms through which malfunctioning of APP, apoE and NACP might lead to synaptic damage and plaque formation in AD.

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References

  • Alvarez J, Moreno RD, Llanos O, Inestrosa NC, Brandan E, Colby T Esch FS (1992) Axonal sprouting induced in the sciatic nerve by the amyloid precursor protein (APP) and other antiproteases. Neurosci Lett 144: 130 – 134

    Article  PubMed  CAS  Google Scholar 

  • Alzheimer A (1907) Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie 64: 146 – 148

    Google Scholar 

  • 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 nonneural tissues from Alzheimer’s disease and control subjects. Ann Neurol 30: 686 – 693

    Article  PubMed  CAS  Google Scholar 

  • 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 – 639

    PubMed  CAS  Google Scholar 

  • Arriagada PV, MarzloffK, Hyman BT (1992b) Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42: 1681 – 1688

    CAS  Google Scholar 

  • Askanas V, Engel WK, Alvarez RB (1992) Strong immunoreactivity of β-amyloid precursor protein, including the β-amyloid protein sequence, at human neuromuscular junctions. Neurosci Lett 143: 96 – 100

    Article  PubMed  CAS  Google Scholar 

  • Balcar VJ, Li Y (1992) Heterogeneity of high affinity of L-glutamate and L-aspartate in the mammalian central nervous system. Life Sci 51: 1467 – 1478

    Article  PubMed  CAS  Google Scholar 

  • Beach TG, Walker R, McGeer EG (1989) Patterns of gliosis in Alzheimer’s disease and aging cerebrum. Glia 2: 420 – 436

    Article  PubMed  CAS  Google Scholar 

  • Bertrand P, Poirier J, Oda T, Finch CE, Pasinetti CM (1995) Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer’s disease. Mol Brain Res 33: 174 – 178

    Article  PubMed  CAS  Google Scholar 

  • Blessed G, Tomlinson BE, Roth M (1968) The association between quantitative measures of dementia and senile change in the cerebral grey matter of elderly subjects. Br J Psych 114: 797 – 811

    Article  CAS  Google Scholar 

  • Bowes MP, Masliah E, Chen B-L, Otero D, Zivin J, Saitoh T (1994) Reduction of neurological damage by a trophic peptide segment of the amyloid β/A4 protein (APP). Exp Neurol 129: 1 – 8

    Article  Google Scholar 

  • Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82: 239 – 259

    Article  PubMed  CAS  Google Scholar 

  • Card JP, Meade RP, Davis LG (1988) Immunocytochemical localization of the precursor of the precursor protein for β-amyloid in the rat central nervous system. Neuron 1: 835 – 846

    Article  PubMed  CAS  Google Scholar 

  • Chen X, de Silva RHA, Pettenati MJ, Rao PN, St.George-Hyslop P, Roses AD, Xia Y, Horsburgh K, Ueda K, Saitoh T (1995) The human NACP/alpha-synuclein gene: chromosome assignment to 4q21.2-q22 and Taql RFLP analysis. Genomics 26: 425 – 427

    Article  PubMed  CAS  Google Scholar 

  • Clark RF, Goate AM (1993) Molecular genetics of Alzheimer’s disease. Arch Neurol 50: 1164–1172

    PubMed  CAS  Google Scholar 

  • Clark RF, Goate AM (1993) Molecular genetics of Alzheimer’s disease. Arch Neurol 50: 1164–1172 Collaborative G (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 Gen 11: 219 – 222

    Article  Google Scholar 

  • Cowburn R, Hardy J, Roberts P, Briggs R (1988) Presynaptic and postsynaptic glutamatergic function in Alzheimer’s disease. Neurosci Lett 86: 109 – 113

    Article  PubMed  CAS  Google Scholar 

  • Cowburn RF, Hardy JA, Roberts PJ (1990) Glutamatergic neurotransmission in Alzheimer’s disease. Biochem Soc Trans 18: 390 – 392

    PubMed  CAS  Google Scholar 

  • Cross AJ, Skan WJ, Slater P (1986) The association of [3H]d-aspartate binding and high-affinity glutamate uptake in the human brain. Neurosci Lett 63: 121 – 124

    Article  PubMed  CAS  Google Scholar 

  • Cummings BJ, Cotman CW (1995) Image analysis of beta-amyloid load in Alzheimer’s disease and relation to dementia severity. Lancet 346: 1524 – 1528

    Article  PubMed  CAS  Google Scholar 

  • Davies CA, Mann DMA, Sumpter PQ, Yates PO (1987) A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci 78: 151 – 164

    Article  PubMed  CAS  Google Scholar 

  • DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: Correlation with cognitive severity. Ann Neurol 27: 457 – 464

    Article  PubMed  CAS  Google Scholar 

  • Delaere P, Duyckaerts C, Brion JP, Poulain V, Hauw JJ (1989) Tau, paired helical filaments and amyloid in the neocortex: a morphometric study of 15 cases with graded intellectual status in aging and senile dementia of Alzheimer type. Acta Neuropathol 77: 645 – 653

    Article  PubMed  CAS  Google Scholar 

  • Dickson DW, Farlo J, Davies P, Crystal H, Fuld P, Yen SC (1988) Alzheimer disease. A double immuno-histochemical study of senile plaques. Am J Pathol 132: 86 – 101

    PubMed  CAS  Google Scholar 

  • Dickson DW, Crystal HA, Bevona C, Honer W, Vincent I, Davies P (1995) Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 16: 285 – 304

    Article  PubMed  CAS  Google Scholar 

  • Eccles JC (1981) The modular operation of the cerebral neocortex considered as the material basis of mental events. Neuroscience 6: 1839 – 1856

    Article  PubMed  CAS  Google Scholar 

  • Eccles JC (1984) The cerebral neocortex: a theory of its operation. In: Jones EG, Peters A (eds) Cerebral cortex. Volume 2. Functional properties of cortical cells. Plenum Press, New York, pp 1 – 38

    Google Scholar 

  • 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 – 527

    Article  PubMed  CAS  Google Scholar 

  • 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 – 706

    Article  PubMed  CAS  Google Scholar 

  • Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255: 728 – 730

    Article  PubMed  CAS  Google Scholar 

  • Gordon I, Grauer E, Genis I, Sehayek E, Michaelson DM (1995) Memory deficits and cholinergic impairments in apolipoprotein E-deficient mice. Neurosci Lett 199: 1 – 4

    Article  PubMed  CAS  Google Scholar 

  • Greenamyre JT, Porter RHP (1994) Anatomy and physiology of glutamate in the CNS. Neurology 44 (suppl): S7 – S13

    Google Scholar 

  • Gregg RE, Zech LA, Schaefer EJ, Stark D, Wilson D, Brewer HB Jr (1986) Abnormal in vivo metabolism of apolipoprotein E4 in humans. J Clin Invest 78: 815 – 821

    Article  PubMed  CAS  Google Scholar 

  • Hamos JE, DeGennaro LJ, Drachman DA (1989) Synaptic loss in Alzheimer’s disease and other dementias. Neurology 39: 355 – 361

    PubMed  CAS  Google Scholar 

  • Hartmann H, Eckert A, Muller WE (1994) Apolipoprotein E and cholesterol affect neuronal calcium signalling: the possible relationship to beta-amyloid neurotoxicity. Biochem Biophys Res Commun 200: 1185 – 1192

    Article  PubMed  CAS  Google Scholar 

  • 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 – 384

    Article  PubMed  CAS  Google Scholar 

  • 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 – 230

    Google Scholar 

  • Hof PR, Cox K, Morrison JH (1990) Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer’s disease: I. Superior frontal and inferior temporal cortex. J Comp Neurol 301: 44–54

    Article  PubMed  CAS  Google Scholar 

  • Holtzman DM, Pitas RE, Kilbridge J, Nathan B, Mahley RW, Bu G, Schwartz AL (1995) Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line. Proc Natl Acad Sci USA 92: 9480 – 9484

    Article  PubMed  CAS  Google Scholar 

  • Honer WG, Dickson DW, Gleeson J, Davies P (1992) Regional synaptic pathology in Alzheimer’s disease. Neurobiol Aging 13: 375 – 382

    Article  PubMed  CAS  Google Scholar 

  • 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 – 481

    Article  PubMed  CAS  Google Scholar 

  • Hyman BT, Kromer LJ, Van Hoesen GW (1987) Reinnervation of the hippocampal perforant pathway zone in Alzheimer’s disease. Ann Neurol 21: 259 – 267

    Article  PubMed  CAS  Google Scholar 

  • Ignatius MJ, Shooter EM, Pitas RE, Mahley RW (1987) Lipoprotein uptake by neuronal growth cones in vitro. Science 236: 959 – 962

    Article  PubMed  CAS  Google Scholar 

  • Iwai A, Masliah E, Yoshimoto M, De Silva R, Ge N, Kittel A, Saitoh T (1994) The precursor protein of non-Aβ component of Alzheimer’s disease amyloid (NACP) is a presynaptic protein of the central nervous system. Neuron 14: 467 – 475

    Article  Google Scholar 

  • Iwai A, Yoshimoto M, Masliah E, Saitoh T (1995) Non-Aβ component of Alzheimer’s disease amyloid (NAC) is amyloidogenic. Biochemistry 34: 10139 – 10145

    Article  PubMed  CAS  Google Scholar 

  • Iwai A, Masliah E, Sundsmo MP, DeTeresa R, Mallory M, Salmon DP, Saitoh T (1996) The synaptic protein NACP is abnormally expressed during the progression of Alzheimer’s disease. Brain Res 720: 230 – 234

    Article  PubMed  CAS  Google Scholar 

  • Jensen PH, Sorensen ES, Petersen TE, Gliemann J, Rasmussen LK (1995) Residues in the synuclein consensus motif of the alpha synuclein fragment, NAC, participate in transglutaminase-catalysed cross-liking to Alzheimer-disease amyloid beta A4 peptide. Biochem J 310: 91 – 94

    PubMed  CAS  Google Scholar 

  • Kanai Y, Hediger MA (1992) Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360: 467 – 471

    Article  PubMed  CAS  Google Scholar 

  • Kanai Y, Smith CP, Hediger MA (1993) The elusive transporters with a high affinity for glutamate. Trends Neurosci 16: 359 – 365

    Article  Google Scholar 

  • Kanai Y, Stelzner M, Nubberg S, Khawaja S, Hebert SC, Smith CP, Hediger MA (1994) The neuronal and epithelial human high affinity glutamate transporter. J Biol Chem 269: 20599 – 20606

    PubMed  CAS  Google Scholar 

  • Kanai Y, Nussberger S, Romero MF, Boron WF, Hebert SC, Hediger MA (1995) Electrogenic properties of the epithelial and neuronal high affinity glutamate transporter. J Biol Chem 270: 16561 – 16568

    Article  PubMed  CAS  Google Scholar 

  • Kounnas MZ, Moir RD, Rebeck GW, Bush AI, Argaves WS, Tanzi RE, Hyman BT, Strickland DK (1995) LDL receptor-related protein, a multifunctional apoE receptor, binds secreted β-amyloid precursor protein and mediates its degradation. Cell 82: 331 – 340

    Article  PubMed  CAS  Google Scholar 

  • 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 – 229

    Article  PubMed  CAS  Google Scholar 

  • 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 – 8

    Article  PubMed  CAS  Google Scholar 

  • Lin-Lee YC, Kao FT, Cheung P, Chan L (1985) Apolipoprotein E gene mapping and expression: localization of the structural gene to human chromosome 19 and expression of ApoE mRNA in lipoprotein and non lipoprotein-producing tissues. Biochemistry 24: 3751 – 3756

    CAS  Google Scholar 

  • Mahley RW, Innerarity TL (1983) Lipoprotein receptors and cholesterol homeostasis. Biochim Biophys Acta 737: 197 – 222

    PubMed  CAS  Google Scholar 

  • Manfras BJ, Rudert WA, Trucco M, Boehm BO (1994) Cloning and characterization of a glutamate transporter cDNA from human brain and pancreas. Bioch Biophys Acta 1195: 185 – 188

    Article  CAS  Google Scholar 

  • Maroteaux L, Scheller RH (1991) The rat brain synucleins; family of proteins transiently associated with neuronal membrane. Mol Brain Res 11: 335 – 343

    Article  PubMed  CAS  Google Scholar 

  • Masliah E (1995a) Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol Histopathol 10: 509 – 519

    PubMed  CAS  Google Scholar 

  • Masliah E (1995b) The natural evolution of the neurodegenerative alterations in Alzheimer’s disease. Neurobiol Aging 16: 280 – 282

    Article  Google Scholar 

  • Masliah E, Terry R (1993) The role of synaptic proteins in the pathogenesis of disorders of the central nervous system. Brain Pathol 3: 77 – 85

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Terry R (1994) The role of synaptic pathology in the mechanisms of dementia in Alzheimer’s disease. Clin Neurosci 1: 192 – 198

    Google Scholar 

  • Masliah E, Terry RD, DeTeresa RM, Hansen LA (1989) Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci Lett 103: 234 – 239

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Hansen L, Albright T, Mallory M, Terry RD (1991a) Immunoelectron microscopic study of synaptic pathology in Alzheimer disease. Acta Neuropathol 81: 428 – 433

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Mallory M, Hansen L, Alford M, Albright T, DeTeresa R, Terry RD, Baudier J, Saitoh T (1991b) Patterns of aberrant sprouting in Alzheimer disease. Neuron 6: 729 – 739

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Terry RD, Alford M, DeTeresa RM, Hansen LA (1991c) Cortical and subcortical patterns of synaptophysin-like immunoreactivity in Alzheimer disease. Am J Pathol 138: 235 – 246

    PubMed  CAS  Google Scholar 

  • Masliah E, Ellisman M, Carragher B, Mallory M, Young S, Hansen L, DeTeresa R, Terry RD (1992a) Three-dimensional analysis of the relationship between synaptic pathology and neuropil threads in Alzheimer disease. J Neuropathol Exp Neurol 51: 404 – 414

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Mallory M, Ge N, Saitoh T (1992b) Protein kinases and growth associated proteins in plaque formation in Alzheimer’s disease. Rev Neurosci 3: 99 – 107

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Mallory M, Hansen L, Alford M, DeTeresa R, Terry R, Baudier J, Saitoh T (1992c) Localization of amyloid precursor protein in GAP43-immunoreactive aberrant sprouting neurites in Alzheimer’s disease. Brain Res 574: 312 – 316

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Mallory M, Hansen L, Alford M, DeTeresa R, Terry R (1993a) An antibody against phosphorylated neurofilaments identifies a subset of damaged association axons in Alzheimer’s disease. Am J Pathol 142: 871 – 882

    PubMed  CAS  Google Scholar 

  • Masliah E, Miller A, Terry RD (1993b) The synaptic organization of the neocortex in Alzheimer’s disease. Medical Hypotheses 41: 334 – 340

    Article  PubMed  CAS  Google Scholar 

  • 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 – 72

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Iwai A, Mallory M, Ueda K, Saitoh T (1995a) Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer’s disease. Am J Pathol 148: 201 – 210

    Google Scholar 

  • Masliah E, Mallory M, Alford M, Ge N, Mucke L (1995b) Abnormal synaptic regeneration in hAPP695 transgenic and APOE knockout mice. In: Iqbal K, Mortimer JA, Winblad B, Wisniewski HM (eds) Research advances in Alzheimer’s disease and related disorders. John Wiley & Sons Ltd, pp 405 – 414

    Google Scholar 

  • Masliah E, Mallory M, Alfort M, Veinbergs I, Roses AD (1995c) ApoE role in maintaining the integrity of the aging central nervous system. In: Roses AD, Weisgraber KH, Christen Y (eds) Apolipoprotein E and Alzheimer’s disease. Springer-Verlag, Heidelberg, pp 59 – 73

    Google Scholar 

  • Masliah E, Mallory M, Ge N, Alford M, Veinbergs I, Roses AD (1995d) Neurodegeneration in the CNS of apoE-deficient mice. Exp Neurol 136: 107 – 122

    Article  CAS  Google Scholar 

  • Masliah E, Mallory M, Veinbergs I, Miller A, Samuel W (1996a) Alterations in apolipoprotein expression during aging and neurodegeneration. Prog Neurobiol 50: 493 – 503

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Mallory M, Veinbergs I, Miller A, Samuel W (1996a) Alterations in apolipoprotein expression during aging and neurodegeneration. Prog Neurobiol 50: 493 – 503

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Alford M, De Teresa R, Mallory M, Hansen L (1996b) Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s Disease. Ann Neurol 40: 759 – 766

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Westland CE, Rockenstein EM, Abraham CR, Mallory M, Veinberg I, Sheldon E, Mucke L (1997a) Amyloid precursor proteins protect neurons of transgenic nice against acute and chronic excitotoxic injuries in vivo. Neuroscience In press

    Google Scholar 

  • 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 – 2763

    PubMed  CAS  Google Scholar 

  • 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 – 254

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP, Cheng B, Smith-Swintosky VL (1993b) Mechanisms of neurotrophic factor protection against calcium- and free radical- mediated excitotoxic injury: Implications for treating neurodegenerative dissorders. Exp Neurol 124: 89 – 95

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP, Tomaselli KJ, Rydel RE (1993 c) Calcium-destabilizing and neurodegenerative effects of aggregated β-amyloid peptide are attenuated by basic FGF. Brain Res 621: 35–49

    Article  PubMed  CAS  Google Scholar 

  • McKee AC, Kosik KS, Kowall NW (1991) Neuritic pathology and dementia in Alzheimer’s disease. Ann Neurol 30: 156 – 165

    Article  PubMed  CAS  Google Scholar 

  • Morris JC, Storandt M, McKeel DW Jr, Rubin EH, Price JL, Grant EA, Berg L (1996) Cerebral amyloid deposition and diffuse plaques in “normal” aging: Evidence for presymptomatic and very mild Alzheimer’s disease. Neurology 46: 707 – 719

    PubMed  CAS  Google Scholar 

  • Morrison JH, Lewis DA, Campbell MJ (1987) Distribution of neurofibrillary tangles and nonphos-phorylated neurofilament protein-immunoreactive neurons in cerebral cortex: implications for loss of corticocortical circuits in Alzheimer’s disease. In: Davies P, Finch CE (eds) Molecular neuropathology of aging. Branbury Report, Vol. 27. Cold Springs Harbor Laboratory, New York, pp 109 – 124

    Google Scholar 

  • 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 – 167

    Article  PubMed  CAS  Google Scholar 

  • Mucke L, Abraham CR, Ruppe MD, Rockenstein EM, Toggas SM, Alford M, Masliah E (1995) Protection against HIV-1 gpl20-induced brain damage by neuronal overexpression of human amyloid precursor protein (hAPP). J Exp Med 181: 1551 – 1556

    Article  PubMed  CAS  Google Scholar 

  • Nakajo S, Tsukada K, Ornata K, Nakamura Y, Nakaya K (1993) A new brain-specific 14-kDA protein is a phosphoprotein. Its complete amino acid sequence and evidence for phosporylation. Eur J Bio-chem 217: 1057 – 1063

    CAS  Google Scholar 

  • Nathan BP, Bellosta S, Sanan DA, Weisgraber KH, Mahley RW, Pitas RE (1994) Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264: 850 – 852

    Article  PubMed  CAS  Google Scholar 

  • Neary D, Snowdon JS, Mann DMA, Bowen DM, Sims NR, Northen B, Yates PO, Davison AN (1986) Alzheimer’s disease: a correlative study. J Neurol Neurosurg Psych 49: 229 – 237

    Article  CAS  Google Scholar 

  • Paik Y-K, Chang DJ, Reardon CA, Davies GE, Mahley RW, Taylor JM (1985) Nucleotide sequence and structure of the human apolipoprotein E gene. Proc Natl Acad Sci USA 82: 3445 – 3449

    Article  CAS  Google Scholar 

  • 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 – 265

    Article  PubMed  CAS  Google Scholar 

  • Pines G, Danbolt NC, Bjoras M, Zhang Y, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J, Seeberg E, Kanner BI (1992) Cloning and expression of a rat brain L-glutamate transporter. Nature 360: 464 – 467

    Article  PubMed  CAS  Google Scholar 

  • Poirier J (1994) Apolipoprotein E in animal models of CNS injury and in Alzheimer’s disease. Trends Neurosci 17: 525 – 530

    CAS  Google Scholar 

  • Poirier J, Baccichet A, Dea D, Gauthier S (1993) Cholesterol synthesis and lipoprotein reuptake during synaptic remodeling in hippocampus in adult rats. Neurosci 55: 81 – 90

    Article  CAS  Google Scholar 

  • Poirier J, Delisle M-C, Quirion R, Aubert I, Farlow M, Lahiri D, Hui S, Bertrand P, Nalbantoglu J, Gilfix BM, Gauthier S (1995) Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci USA 92: 12260 – 12264

    Article  PubMed  CAS  Google Scholar 

  • Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11: 575 – 580

    Article  PubMed  CAS  Google Scholar 

  • Roch J-M, Masliah E, Roch-Levecq A-C, Sundsmo MP, Otero DAC, Veinbergs I, Saitoh T (1994) Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid β/A4 protein precursor. Proc Natl Acad Sci USA 91: 7650 – 7654

    Article  Google Scholar 

  • Roses AD, Einstein G, Gilbert J, Goedert M, Han S-H, Huang D, Hulette C, Masliah E, Pericak-Vance MA, Saunders AM, Schmechel DE, Strittmatter WJ, Weisgraber KH, Xi P-T (1996) Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism. Ann NY Acad Sci 777: 147 – 157

    Article  Google Scholar 

  • 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 – 6595

    Article  PubMed  CAS  Google Scholar 

  • Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, Nash N, Kuncl RW (1994) Localization of neuronal and glial glutamate transporters. Neuron 13: 713 – 725

    Article  PubMed  CAS  Google Scholar 

  • Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38: 73 – 84

    Article  PubMed  CAS  Google Scholar 

  • Saitoh T, Roch J-M, Lin LW, Ninomiya H, Otero DAC, Yamamoto K, Masliah E (1994) The biological function of amyloid β/A4 protein in precursor. In: Masters CL, Beyreuther K, Trillet M, Christen Y (eds) Amyloid protein precursor in development, aging and Alzheimer’s disease. Springer-Verlag, Heidelberg, pp 90 – 99

    Google Scholar 

  • Samuel W, Masliah E, Terry R (1994a) Hippocampal connectivity and Alzheimer’s dementia: effects of pathology in a two-component model. Neurology 44: 2081 – 2088

    PubMed  CAS  Google Scholar 

  • Samuel W, Terry RD, DeTeresa R, Butters N, Masliah E (1994b) Clinical correlates of cortical and nucleus pathology in Alzheimer dementia. Arch Neurol 51: 772 – 778

    PubMed  CAS  Google Scholar 

  • 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 – 1472

    PubMed  CAS  Google Scholar 

  • Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 90: 9649 – 9653

    Article  CAS  Google Scholar 

  • Schubert W, Prior R, Weidemann A, Dircksen H, Multhaup G, Masters CL, Beyreuther K (1991) Localization of Alzheimer beta A4 amyloid precursor protein at central and peripheral synaptic sites. Brain Res 563: 184 – 194

    Article  PubMed  CAS  Google Scholar 

  • Scott HL, Tannenberg AEG, Dodd PR (1995) Variant forms of neuronal glutamate transporter sites in Alzheimer’s disease cerebral cortex. J Neurochem 64: 2193 – 2202

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (1989) Amyloid β protein precursor and the pathogenesis of Alzheimer’s disease. Cell 58: 611 – 612

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ 1993 ) Physiological production of the β-amyloid protein and the mechanisms of Alzheimer’s disease. Trends Neurosci 16: 403 – 409

    Article  PubMed  CAS  Google Scholar 

  • Shashidharan P, Huntley GW, Meyer T, Morrison JH, Platakis A (1994) Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain. Brain Res 662: 245 – 250

    Article  PubMed  CAS  Google Scholar 

  • Shimokawa M, Yanagisawa K, Nishiye H, Miyatake T (1993) Identification of amyloid precursor protein in synaptic plasma membrane. Biochem Biophys Res Commun 196: 240 – 244

    Article  PubMed  CAS  Google Scholar 

  • 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 – 494

    Article  PubMed  CAS  Google Scholar 

  • Small DH, Nurcombe V, Reed G, Clarris H, Moir R, Beyreuther K, Masters CL (1994) A heparin-binding domain in the amyloid protein precursor of Alzheimer’s disease is involved in the regulation of neurite outgrowth. J Neurosci 14: 2117 – 2127

    PubMed  CAS  Google Scholar 

  • Smith-Swintosky VL, Pettigrew LC, Craddock SD, Culwell AR, Rydel RE, Mattson MP (1994) Secreted forms of β-amyloid precursor protein protect against ischemic brain injury. J Neurochem 63: 781 – 784

    Article  PubMed  CAS  Google Scholar 

  • Storck T, Schulte S, Hofman K, Stoffel W (1992) Structure, expression, and functional analysis of a Nat+-dependent glutamate/aspartate transporter from rat brain. Proc Natl Acad Sci USA 89: 10955 – 10959

    Article  PubMed  CAS  Google Scholar 

  • Strickland DK, Kounas MZ, Argaves WS (1995) LDL receptor-related protein: a multiligand receptor for lipoprotein and proteinase catabolism. FASEB J 9: 890 – 898

    PubMed  CAS  Google Scholar 

  • Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-aviditiy binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90: 1977 – 1981

    Article  PubMed  CAS  Google Scholar 

  • Strittmatter WJ, Weisgraber KH, Goedert M, Saunders AM, Huang D, Corder EH, Dong LM, Jakes R, Alberts MJ, Gilbert JR (1994) Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Exp Neurol 125: 163 – 171

    Article  CAS  Google Scholar 

  • Suzuki K, Terry RD (1967) Fine structural localization of acid phosphatase in senile plaques in Alzheimer’s presenile dementia. Acta Neuropathol 8: 276 – 284

    Article  PubMed  CAS  Google Scholar 

  • Tanzi RE, McClatchey AI, Lamperti ED, Villa-Komaroff L, Gusella JF, Neve RL (1988) Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer’s disease. Nature 331: 528 – 530

    Article  PubMed  CAS  Google Scholar 

  • Terry RD, Gonatas NK, Weiss M (1964) Ultrastructural studies in Alzheimer’s presenile dementia. Am J Pathol 44: 269 – 297

    PubMed  CAS  Google Scholar 

  • 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 Alzheime’s Disease and Related Conditions. J & A Churchill, London, pp 145 – 168

    Google Scholar 

  • 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 – 192

    Article  PubMed  CAS  Google Scholar 

  • 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 – 580

    Article  PubMed  CAS  Google Scholar 

  • Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Otero D, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of a novel amyloid component in Alzheimer’s disease. Proc Natl Acad Sci USA 90: 11282 – 11286

    Article  PubMed  CAS  Google Scholar 

  • Ueda K, Saitoh T, Mori H (1994) Tissue-dependent alternative splicing of mRNA for NACP, the precursor of non-A beta component of Alzheimer’s disease amyloid. Biochem Biophys Res Commun 205: 1366 – 1372

    Article  PubMed  CAS  Google Scholar 

  • Van Nostrand WE, Wagner SL, Suzuki M, Choi BH, Farrow JS, Geddes JW, Cotman CW, Cunningham DD (1989) Protease nexin-II, a potent antichymotripsin, shows identity to amyloid β protein. Nature 341: 546 – 548

    Article  PubMed  Google Scholar 

  • Xia Y, de Silva HAR, Rosi BL, Yamaoka LH, Rimmler JB, Pericak-Vance MA, Roses AD, Chen X, Masliah E, DeTeresa R, Iwai A, Sundsmo M, Thomas RG, Hofstetter CR, Gregory E, Hansen LA, Katzman R, Thal LJ, Saitoh T (1996) Genetic studies in Alzheimer’s disease with an NACP/alpha-synuclein polymorphism. Ann Neurol 40: 207 – 215

    Article  PubMed  CAS  Google Scholar 

  • Yamada T, Kondo A, Takamatsu J, Tateishi J, Goto I (1995) Apolipoprotein E mRNA in the brains of patients with Alzheimer’s disease. J Neurol Sci 129: 56 – 61

    CAS  Google Scholar 

  • 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 – 549

    Article  PubMed  CAS  Google Scholar 

  • Yoshimoto M, Iwai A, Kang D, Otero DAC, Xia Y, Saitoh T (1995) NACP, the precursor protein of non-amyloid β/A4 protein (Aβ) component of Alzheimer disease amyloid, binds Aβ and stimulates Aβ aggregation. Proc Natl Acad Sci USA 92: 9141 – 9145

    Article  PubMed  CAS  Google Scholar 

  • Zannis VL, Breslow JL (1981) Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variations and post-translational modification. Biochemistry 20: 1033 – 1041

    Article  PubMed  CAS  Google Scholar 

  • Zhan SS, Beyreuther K, Schmitt HP (1993) Quantitative assessment of the synaptophysin immunoreactivity of the cortical neuropil in various neurodegenerative disorders with dementia. Dementia 4: 66 – 74

    PubMed  CAS  Google Scholar 

  • Zhong Z, Quon D, Higgins LS, Higaki J, Cordeil B (1994) Increased amyloid production from aberrant β-amyloid precursor proteins. J Biol Chem 269: 12179 – 12184

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Departments of Neurosciences and Pathology, University of California, San Diego, School of Medicine, La Jolla, California, 92093-0624, USA

    E. Masliah

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  1. E. Masliah
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  2. M. Mallory
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  3. M. Alford
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  4. R. DeTeresa
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  5. A. Iwai
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  6. T. Saitoh
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Editors and Affiliations

  1. Nuerology Service, Massachusetts General Hospital, Fruit Street, 02114, Boston, MA, USA

    B. T. Hayman M.D., Ph.D.

  2. Laboratoire de Neuropathologie R. Escourolle, Hôpital de La Salpêtrière, Blvd. de l’Hôpital, 75651, Paris Cedex 16, France

    C. Duyckaerts M.D., Ph.D.

  3. Fondation IPSEN, 24, rue Erlanger, 75651, Paris Cedex 16, France

    Y. Christen Ph.D.

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Masliah, E., Mallory, M., Alford, M., DeTeresa, R., Iwai, A., Saitoh, T. (1997). Molecular Mechanisms of Synaptic Disconnection in Alzheimer’s Disease. In: Hayman, B.T., Duyckaerts, C., Christen, Y. (eds) Connections, Cognition and Alzheimer’s Disease. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60680-9_9

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