Zusammenfassung
Ausgangspunkt der Forschung zu molekularbiologischen Grundlagen der Alzheimer-Krankheit waren die charakteristischen histopathologischen Merkmale der Erkrankung, die darauf hinweisen, daß das β-Amyloid (Aβ) und das Amyloidvorläuferprotein (APP) sowie das tau-Protein auf molekularer Ebene am Krankheitsgeschehen beteiligt sind. Durch die molekulargenetische Charakterisierung der verschiedenen genetischen Ursachen der Erkrankung wurde dann nicht nur die zu vermutende pathogenetische Bedeutung des Aβ weitgehend bestätigt, sondern es konnten auch weitere an der Auslösung der Alzheimer-Krankheit beteiligte Gene bzw. Genprodukte identifiziert werden, die Präseniline und das Apolipoprotein E, dessen ε4-Form als Risikofaktor wirkt.
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Literatur
**Alzheimer A (1907) Über eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiatr Psych Gerichtl Med 64:146–148
Auld DS, Kar S, Quirion R (1998) Beta-amyloid peptides as direct cholinergic neuromodulators: a missing link? Trends Neurosci 21:43–49
Bales KR, Verina T, Dodel RC et al. (1997) Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet 17:263–264
Banati RB, Gehrmann J, Czech C et al. (1993) Early and rapid de novo synthesis of Alzheimer beta A4-amyloid precursor protein (APP) in activated microglia. Glia 9:199–210
Banati RB, Gehrmann J, Wiessner C, Hossmann KA, Kreutzberg GW (1995) Glial expression of the beta-amyloid precursor protein (APP) in global ischemia. J Cereb Blood Flow Metab 15:647–654
Barger SW, Mattson MP (1996) Induction of neuroprotective kappa B-dependent transcription by secreted forms of the Alzheimer’s beta-amyloid precursor. Mol Brain Res 40:116–126
Baumeister R, Leimer U, Zweckbronner J, Jakubek C, Grünberg J, Haass C (1997) The sel-12 mutant phenotype of C. elegans is rescued independent of proteolytic processing by wt but not mutant presenilin. Genes Function 1:149–159
Behl C (1997) Amyloid beta-protein toxicity and oxidative stress in Alzheimer’s disease. Cell Tissue Res 290:471–480
Behl C, Davis JB, Lesley R, Schubert D (1994) Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77:817–827
Billingsley ML, Kincaid RL (1997) Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem J 323:577–591
Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101:1371–1378
Blacker D, Haines JL, Rodes L et al. (1997) ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative. Neurology 48:139–147
Blanchard BJ, Konopka G, Russell M, Ingram VM (1997) Mechanism and prevention of neurotoxicity caused by beta-amyloid peptides: relation to Alzheimer’s disease. Brain Res 776:40–50
Borchelt DR, Thinakaran G, Eckman CB et al. (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate A beta 1–42/1–40 ratio in vitro and in vivo. Neuron 17:1005–1013
Borchelt DR, Ratovitski T, Vanlare J et al. (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–945
*Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278
Breitner JCS (1996) The role of antiinflammatory drugs in the prevention and treatment of Alzheimer’s disease. Annu Rev Med 47:401–411
Bullido MJ, Artiga MJ, Recuero M et al. (1998) A polymorphism in the regulatory region of APOE associated with risk for Alzheimer’s dementia. Nat Genet 18:69–71
Busciglio J, Lorenzo A, Yeh J, Yankner BA (1995) Beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14:879–888
Bush AI, Multhaup G, Moir RD et al. (1993) A novel zinc (II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer’s disease. J Biol Chem 268:16109–16112
Buxbaum JD, Gandy SE, Cicchetti P et al. (1990) Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. Proc Natl Acad Sci USA 87:6003–6006
Buxbaum JD, Ruefli AA, Parker CA, Cypess AM, Greengard P (1994) Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. Proc Natl Acad Sci USA 91:4489–4493
*Cai XD, Golde TE, Younkin SG (1993) Release of excess amyloid P protein from a mutant amyloid β protein β precursor. Science 259:514–516
Campion D, Martin C, Heilig R et al. (1995) The NACP/ synuclein gene: Chromosomal assignment and screening for alterations in Alzheimer disease. Genomics 26:254–257
Capell A, Saffrich R, Olivo JC et al. (1997) Cellular expression and proteolytic processing of presenilin proteins is developmentally regulated during neuronal differentiation.J Neurochem 69:2432–2440
Capell A, Grunberg J, Pesold B et al. (1998) The proteolytic fragments of the Alzheimer’s disease-associated presenilin-1 form heterodimers and occur as a 100–150-kDa molecular mass complex. J Biol Chem 273:3205–3211
Caporaso GL, Gandy SE, Buxbaum JD, Ramabhadran TV, Greengard P (1992) Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. Proc Natl Acad Sci USA 89:3055–3059
Castano EM, Prelli F, Wisniewski T, Golabek A, Kumar RA, Soto C, Frangione B (1995) Fibrillogenesis in Alzheimer’s disease of amyloid beta peptides and apolipoprotein E. Biochem J 306:599–604
Chartier Harlin MC, Crawford F, Houlden H et al (1991) Early-on-set Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353:844–846
*Citron M, Oltersdorf T, Haass C et al. (1992) Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature 360:672–674
Citron M, Westaway D, Xia W et al. (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 3:67–72
Clark RF, Hutton M, Fuldner RA et al. (1995) The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet 11:219–222
Conlon RA, Reaume AG, Rossant J (1995) Notch1 is required for the coordinate segmentation of somites. Development 121:1533–1545
Cook DG, Sung JC, Golde TE et al. (1996) Expression and analysis of presenilin 1 in a human neuronal system: localization in cell bodies and dendrites. Proc Natl Acad Sci USA 93:9223–9228
*Cook DG, Forman MS, Sung JC et al. (1997) Alzheimer’s A beta (1–42) is generated in the endoplasmic reticulum/intermediate com-partment of NT2 N cells. Nature Med 3:1021–1023
Corder EH, Saunders AM, Strittmatter WJ et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923
*Cruts M, Duijn CM van, Backhovens H et al. (1998) Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population based study of presenile Alzheimer disease. Hum Mol Genet 7:43–51
Davis RE, Miller S, Herrnstadt C et al. (1997) Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. Proc Natl Acad Sci USA 94:4526–4531
*De Strooper B, Saftig P, Craessaerts K et al. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387–390
Doan A, Thinakaran G, Borchelt DR et al. (1996) Protein topology of presenilin 1. Neuron 17:1023–1030
Drewes G, Lichtenberg Kraag B et al. (1992) Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J 11:2131–2138
Drewes G, Trinczek B, Illenberger S et al. (1995) Microtubule-associated protein microtubule affinity-regulating kinase (pno (mark)) — A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. J Biol Chem 270:7679–7688
Duff K, Eckman C, Zehr C et al. (1996) Increased amyloid-beta 42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–713
Duijn CM van, Clayton D, Chandra V et al. (1991) Familial aggregation of Alzheimer’s disease and related disorders: a collaborative re-analysis of case-control studies. Int J Epidemiol 20(Suppl 1): S13–S20
Dyrks T, Weidemann A, Multhaup G et al. (1988) Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer’s disease. EMBO J 7:949–957
Dyrks T, Dyrks E, Hartmann T, Masters C, Beyreuther K (1992) Amyloidogenicity of βA4 and βA4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation. J Biol Chem 267:18210–18217
Eckman CB, Mehta ND, Crook R et al. (1997) A new pathogenic mutation in the APP gene (1716 V) increases the relative proportion of A beta 42(43). Hum Mol Genet 6:2087–2089
Efthimiopoulos S, Felsenstein KM, Sambamurti K, Robakis NK, Refolo LM (1994) Study of the phorbol ester effect on Alzheimer amyloid precursor processing: sequence requirements and involvement of a cholera toxin sensitive protein. J Neurosci Res 38:81–90
Efthimiopoulos S, Punj S, Manolopoulos V, Pangalos M, Wang GP, Refolo LM, Robakis NK (1996) Intracellular cyclic AMP inhibits constitutive and phorbol ester-stimulated secretory cleavage of amyloid precursor protein. J Neurochem 67:872–875
Elkhoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382:716–719
*Esch FS, Keim PS, Beattie EC et al. (1990) Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248:1122–1124
Etcheberrigaray R, Ito E, Kim CS, Alkon DL (1994) Soluble beta-amyloid induction of Alzheimer’s phenotype for human fibroblast K+ channels. Science 264:276–279
Evans KC, Berger EP, Cho CG, Weisgraber KH, Lansbury PT Jr (1995) Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease. Proc Natl Acad Sci USA 92:763–767
Evin G, Beyreuther K, Masters CL (1994) Alzheimer’s disease amyloid precursor protein (AftPP): proteolytic processing, secretases and βA4 amyloid production. Int J Exp Clin Invest 1:263–280
Farrer LA, Cupples LA, Haines JL et al. (1997) Effects of age, sex, ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: A meta-analysis. JAMA 278:1349–1356
Feany MB, Dickson DW (1996) Neurodegenerative disorders with extensive tau pathology: A comparative study and review. Ann Neurol 40:139–148
Frautschy SA, Yang FS, Irrizarry M, Hyman B, Saido TC, Hsiao K, Cole GM (1998) Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 152:307–317
Gabuzda D, Busciglio J, Chen LB, Matsudaira P, Yankner BA (1994) Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 269:13623–13628
*Games D, Adams D, Alessandrini R et al. (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373:523–527
*Goate A, Chartier Harlin MC, Mullan M et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706
Goedert M (1995) Molecular dissection of the neurofibrillary lesions of Alzheimer’s disease. Arzneimittelforschung 45/1:403–409
*Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J 8:393–399
Goedert M, Cohen ES, Jakes R, Cohen P (1992) p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer’s disease. FEBS Lett 312:95–99
Goedert M, Jakes R, Spillantini MG, Hasegawa M, Smith MJ, Crowther RA (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383:550–553
Gong CX, Grundke Iqbal I, Damuni Z, Iqbal K (1994 a) Dephosphorylation of microtubule-associated protein tau by protein phosphatase-1 and -2C and its implication in Alzheimer disease. FEBS Lett 341:94–98
Gong CX, Grundke Iqbal I, Iqbal K (1994b) Dephosphorylation of Alzheimer’s disease abnormally phosphorylated tau by protein phosphatase-2 A. Neuroscience 61:765–772
Goodman Y, Mattson MP (1994) Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. Exp Neurol 128:1–12
Goto S, Yamamoto H, Fukunaga K, Iwasa T, Matsukado Y, Miyamoto E (1985) Dephosphorylation of microtubule-associated protein 2, tau factor, and tubulin by calci-neurin. J Neurochem 45:276–283
Greenwood JA, Scott CW, Spreen RC, Caputo CB, Johnson GV (1994) Casein kinase II preferentially phosphorylates human tau isoforms containing an amino-terminal insert. Identification of threonine 39 as the primary phosphate acceptor. J Biol Chem 269:4373–4380
Grilli M, Ribola M, Alberici A, Valerio A, Memo M, Spano PF (1995) Identification and characterization of a kappa B/Rel binding site in the regulatory region of the amyloid precursor protein gene. J Biol Chem 270:26774–26777
Grunberg J, Walter J, Loetscher H, Deuschle U, Jacobsen H, Haass C (1998) Alzheimer’s disease associated presenilin-1 holoprotein and its 18–20 kDa C-terminal fragment are death substrates for proteases of the caspase family. Biochemistry 37:2263–2270
Grundke Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM (1986 a) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261:6084–6089
Grundke Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986 b) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917
Guo Q, Furukawa K, Sopher BL et al. (1996) Alzheimer’s PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide. Neuroreport 8:379–383
*Haass C (1997) Presenilins: genes for life and death. Neuron 18:687–690
Haass C, Selkoe DJ (1993) Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75:1039–1042
Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ (1992 a) Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357:500–503
*Haass C, Schlossmacher MG, Hung AY et al. (1992 b) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322–325
Haass C, Hung AY, Selkoe DJ, Teplow DB (1994) Mutations associated with a locus for familial Alzheimer’s disease result in alternative processing of amyloid beta-protein precursor. J Biol Chem 269:17741–17748
Han SH, Einstein G, Weisgraber KH et al. (1994) Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study. J Neuropathol Exp Neurol 53:535#x2013;544
*Hardy J (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 20:154–159
*Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12:383–388
Haring R, Gurwitz D, Barg J et al. (1995) NGF promotes amyloid precursor protein secretion via muscarinic receptor activation. Biochem Biophys Res Commun 213:15–23
Harris ME, Hensley K, Butterfield DA, Leedle RA, Carney JM (1995) Direct evidence of oxidative injury produced by the Alzheimer’s beta-amyloid peptide (1–40) in cultured hippocampal neurons. Exp Neurol 131:193–202
*Hartmann T, Bergsdorf C, Tienari P et al. (1995) Alternative splicing of APP influences polarised sorting and βA4 production. Soc Neurosci Abstracts 21:504
Hartmann T, Bieger SC, Bruhl B et al. (1997) Distinct sites of intracellular production for Alzheimer’s disease A beta 40/42 amyloid peptides. Nat Med 3:1016–1020
Hasegawa M, Morishima Kawashima M, Takio K, Suzuki M, Titani K, Ihara Y (1992) Protein sequence and mass spectrometric analyses of tau in the Alzheimer’s disease brain. J Biol Chem 267:17047–17054
Heintz N, Zoghbi H (1997) Alpha-synuclein — a link between Parkinson and Alzheimer diseases? Nat Genet 16:325–327
Hendriks L, Duijn CM van, Cras P et al. (1992) Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene. Nat Genet 1:218–221
Hirano M, Shtilbans A, Mayeux R, Davidson MM, Dimauro S, Knowles JA, Schon EA (1997) Apparent mtDNA heteroplasmy in Alzheimer’s disease patients and in normals due to PCR amplification of nucleus-embedded mtDNA pseudogenes. Proc Natl Acad Sci USA 94:14894–14899
*Hofman A, Ott A, Breteler MM et al. (1997) Atherosclerosis, apolipoprotein E, prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet 349:151–154
Holcomb L, Gordon MN, McGowan E et al. (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100
Holtzman DM, Pitas RE, Kilbridge J, Nathan B, Mahley RW, Bu GJ, 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
Houlden H, Crook R, Backhovens H et al. (1998) ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer’s disease families. Am J Med Genet 81:117–121
Hoyer S (1998) Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J Neural Transm 105:415–422
Hrabe de Angelis M, McIntyre JN, Gossler A (1997) Maintenance of somite borders in mice requires the Delta homologue DII1. Nature 386:717–721
Hsiao KK, Borchelt DR, Olson K et al. (1995) Age related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 15:1203–1218
Hsiao K, Chapman P, Nilsen S et al. (1996) Correlative memory deficits, A beta elevation, amyloid plaques in transgenic mice. Science 274:99–102
Hung AY, Haass C, Nitsch RM et al. (1993) Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J Biol Chem 268:22959–22962
Hung AY, Selkoe DJ (1994) Selective ectodomain phosphorylation and regulated cleavage of beta-amyloid precursor protein. EMBO J 13:534–542
*Hutton M, Hardy J (1997) The presenilins and Alzheimer’s disease. Hum Mol Genet 6:1639–1646
Hutton M, Busfield F, Wragg M et al. (1996) Complete analysis of the presenilin 1 gene in early onset Alzheimer’s disease. Neuroreport 7:801–805
*Hutton M, Lendon CL, Rizzu P et al. (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705
Ida N, Hartmann T, Pantel J et al. (1996) Analysis of heterogeneous beta A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem 271:22908–22914
Ikezu T, Okamoto T, Komatsuzaki K, Matsui T, Martyn JAJ, Nishimoto I (1996) Negative transactivation of cAMP response element by familial Alzheimer’s mutants of APP. EMBO J 15:2468–2475
Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT (1997) APP(Sw) transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CAi. J Neuropathol Exp Neurol 56:965–973
Iversen LL, Mortishiresmith RJ, Pollack SJ, Shearman MS (1995) The toxicity in vitro of beta-amyloid protein. Biochem J 311:1–16
Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aß monoclonals: evidence that an initially deposited species is Aβ42(43). Neuron 13:45–53
Iwatsubo T, Mann DMA, Odaka A, Suzuki N, Ihara Y (1995) Amyloid ß protein (Aß) deposition: Aβ42(43) precedes Aβ40 in Down syndrome. Ann Neurol 37:294–299
Jacobsen JS, Spruyt MA, Brown et al. (1994) The release of Alzheimer’s disease beta amyloid peptide is reduced by phorbol treatment. J Biol Chem 269:8376–8382
Jameson L, Frey T, Zeeberg B, Dalldorf F, Caplow M (1980) Inhibition of microtubule assembly by phosphorylation of microtubule-associated proteins. Biochemistry 19:2472–2479
Jensen PH, Hojrup P, Hager H et al. (1997) Binding of Abeta to alpha- and beta-synucleins: identification of segments in alpha-synuclein/NAC precursor that bind Abeta and NAC. Biochem J 323:539–546
Jin LW, Ninomiya H, Roch JM, Schubert D, Masliah E, Otero DA, Saltoh T (1994) Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci 14:5461–5470
Kaltschmidt B, Baeuerle PA, Kaltschmidt C (1993) Potential involvement of the transcription factor NF-kappa B in neurological disorders. Mol Aspects Med 14:171–190
Kaltschmidt B, Uherek M, Volk B, Baeuerle PA, Kaltschmidt C (1997) Transcription factor NF-kappa B is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc Natl Acad Sci U S A 94:2642–2647
*Kang J, Lemaire HG, Unterbeck et al. (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736
Kar S, Seto D, Gaudreau P, Quirion R (1996) Beta-amyloid-related peptides inhibit potassium-evoked acetylcholine release from rat hippocampal slices. J Neurosci 16:1034–1040
Kibbey MC, Jucker M, Weeks BS, Neve RL, Van Nostrand WE, Kleinman HK (1993) Beta-amyloid precursor protein binds to the neurite-promoting IKVAV site of laminin. Proc Natl Acad Sci USA 90:10150–10153
Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197:192–193
Kim TW, Tanzi RE (1997) Presenilins and Alzheimer’s disease. Curr Opin Neurobiol 7:683–688
Kim TW, Pettingell WH, Hallmark OG, Moir RD, Wasco W, Tanzi RE (1997 a) Endoproteolytic cleavage and proteasomal degradation of presenilin 2 in transfected cells. J Biol Chem 272:11006–11010
Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE (1997b) Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Science 277:373–376
Kitaguchi N, Takahashi Y, Tokushima Y, Shiojiri S, Ito H (1988) Novel precursor of Alzheimer’s disease amyloid protein shows protease inhibitory activity. Nature 331:530–532
Koch CS von, Zheng H, Chen H et al. (1997) Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging 18:661–669
Konig G, Monning U, Czech et al. (1992) Identification and differential expression of a novel alternative splice isoform of the βA4 amyloid precursor protein (APP) mRNA in leukocytes and brain microglial cells. J Biol Chem 267:10804–10809
Konsortium zur molekulargenetischen Diagnostik der Huntington-Krankheit (1996) Informationsblatt zur molekulargenetischen Diagnostik der Huntington-Krankheit. Med Genet 8:208–209
Kopke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke Iqbal I (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 268:24374–24384
Kosik KS, Joachim CL, Selkoe DJ (1986) Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA 83:4044–4048
Kovacs DM, Fausett HJ, Page KJ et al. (1996) Alzheimer-associated presenilins 1 and 2: Neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat Med 2:224–229
Kruger R, Kuhn W, Muller T et al. (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108
Ladu MJ, Pederson TM, Frail DE, Reardon CA, Getz GS, Falduto MT (1995) Purification of apolipoprotein E attenuates isoformspecific binding to beta-amyloid. J Biol Chem 270:9039–9042
Lambert JC, Pereztur J, Dupire MJ et al. (1997) Distortion of allelic expression of apolipoprotein E in Alzheimer’s disease. Hum Mol Genet 6:2151–2154
Lambert JC, Pasquier F, Cottel D, Frigard B, Amouyel P, Chartier-Harlin MC (1998) A new polymorphism in the APOE promoter associated with risk of developing Alzheimer’s disease. Hum Mol Genet 7–533–540
Lautenschlager NT, Cupples LA, Rao VS et al. (1996) Risk of dementia among relatives of Alzheimer’s disease patients in the MIRAGE study: What is in store for the oldest old? Neurology 46:641–650
Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251:675–678
Lee RKK, Wurtman RJ, Cox AJ, Nitsch RM (1995) Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors. Proc Natl Acad Sci USA 92:8083–8087
Lee MK, Borchelt DR, Kim G et al. (1997) Hyperaccumulation of FAD-linked presenilin 1 variants in vivo. Nat Med 3:756–760
Lehmann DJ, Johnston C, Smith AD (1997) Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer’s disease. Hum Mol Genet 6:1933–1936
Levitan D, Greenwald I (1995) Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 377:351–354
Levitan D, Doyle TG, Brousseau D et al. (1996) Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci USA 93:14940–14944
*Levy E, Carman MD, Fernandez MI et al. (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248:1124–1126
*Levy-Lahad E, Wasco W, Poorkaj P et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269:973–977
Lezoualc’h F, Behl C (1998) Transcription factor NF-kappaB: friend or foe of neurons? Mol Psychiatry 3:15–20
Lezoualc’h F, Sagara Y, Holsboer F, Behl C (1998) High constitutive NF-kappaB activity mediates resistance to oxidative stress in neuronal cells. J Neurosci 18:3224–3232
Li XJ, Greenwald I (1996) Membrane topology of the C-elegans SEL-12 presenilin. Neuron 17:1015–1021
Litersky JM, Johnson GV (1992) Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain. J Biol Chem 267:1563–1568
Loetscher H, Deuschle U, Brockhaus et al. (1997) Presenilins are processed by caspase-type proteases. J Biol Chem 272:20655–20659
Lowenberg K, Waggoner R (1934) Familial organic psychosis (Alzheimer’s type). Arch Neurol Psychiatr 31:737–754
Luo YQ, Hirashima N, Li YH, Alkon DL, Sunderland T, Etcheberrigaray R, Wolozin B (1995) Physiological levels of beta-amyloid increase tyrosine phosphorylation and cytosolic calcium. Brain Res 681:65–74
Luo Y, Sunderland T, Wolozin B (1996) Physiologic levels of beta-amyloid activate phosphatidylino-sitol 3-kinase with the involvement of tyrosine phosphorylation. J Neurochem 67:978–987
Mahdi F, Vannostrand WE, Schmaier AH (1995) Protease nexin-2/amyloid beta-protein precursor inhibits factor Xa in the prothrombinase complex. J Biol Chem 270:23468–23474
Mandelkow EM, Drewes G, Biernat J, Gustke N, Van Lint J, Vandenheede JR, Mandelkow E (1992) Glycogen synthase kinase-3 and the Alzheimer-like state of micro-tubule-associated protein tau. FEBS Lett 314:315–321
Maruyama K, Kametani F, Usami M, Yamao Harigaya W, Tanaka K (1991) „Secretase″, Alzheimer amyloid protein precursor secreting enzyme is not sequence-specific. Biochem Biophys Res Commun 179:1670–1676
Matsuo ES, Shin RW, Billingsley ML, Van deVoorde A, O’Connor M, Trojanowski JQ, Lee VM (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron 13:989–1002
Mattila KM, Forsell C, Pirttila T et al. (1998) The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer’s disease. Neurobiol Aging 19(Suppl 4S), abstract no 362
*Mattson MP (1997) Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 77:1081–1132
Mattson MP, Barger SW, Cheng B, Lieberburg I, Smith Swintosky VL, Rydel RE (1993 a) Beta-amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer’s disease. Trends Neurosci 16:409–414
Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I, Rydel RE (1993b) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron 10:243–254
Mattson MP, Guo Q, Furukawa K, Pedersen WA (1998) Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer’s disease. J Neurochem 70:1–14
*Mayeux R, Saunders AM, Shea S et al. (1998) Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. N Engl J Med 338:506–511
McKeith IG, Galasko D, Kosaka et al. (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 47:1113–1124
McKhann G, Drachman D, Folstein M, Kargman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944
Milward EA, Papadopoulos R, Fuller SJ, Moir RD, Small D, Beyreuther K, Masters CL (1992) The amyloid protein precursor of Alzheimer’s disease is a mediator of the effects of nerve growth factor on neurite outgrowth. Neuron 9:129–137
Monning U, Sandbrink R, Weidemann A, Banati RB, Masters CL, Beyreuther K (1995) Extracellular matrix influences the biogenesis of amyloid precursor protein in microglial cells. J Biol Chem 270:7104–7110
Montoya SE, Aston CE, Dekosky ST, Kamboh MI, Lazo JS, Ferrell RE (1998) Bleomycin hydrolase is associated with risk of sporadic Alzheimer’s disease. Nat Genet 18:211–212
Morishima Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Titani K, Iharae Y (1995) Proline-directed and non-proline-directed phosphorylation of PHF-tau. J Biol Chem 270:823–829
Motter R, Vigopelfrey C, Kholodenko D et al. (1995) Reduction of beta-amyloid peptide (42), in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 38:643–648
*Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1:345–347
Müller-Hill B, Beyreuther K (1989) Molecular biology of Alzheimer’s disease. Annu Rev Biochem 58:287–307
Multhaup G (1994) Identification and regulation of the high affinity binding site of the Alzheimer’s disease amyloid protein precursor (APP) to glycosaminoglycans. Biochimie 76:304–311
Multhaup G, Schlicksupp A, Hesse L, Beher D, Ruppert T, Masters CL, Beyreuther K (1996) The amyloid precursor protein of Alzheimer’s disease in the reduction of copper (II) to copper (I) Science 271:1406–1409
Murrell J, Farlow M, Ghetti B, Benson MD (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 254:97–99
Narindrasorasak S, Lowery D, Gonzalez DeWhitt P, Poorman RA, Greenberg B, Kisilevsky R (1991) High affinity interactions between the Alzheimer’s beta-amyloid precursor proteins and the basement membrane form of heparan sulfate proteoglycan. J Biol Chem 266:12878–12883
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
Nathan BP, Chang KC, Bellosta S, Brisch E, Ge NF, Mahley RW, Pitas RE (1995) The inhibitory effect of apolipoprotein E4 on neurite outgrowth is associated with microtubule depolymerization. J Biol Chem 270:19791–19799
**NIA/AA (1996) Apolipoprotein E genotyping in Alzheimer’s disease. National Institute on Aging/ Alzheimer’s Association Working Group. Lancet 347:1091–1095
Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Okamoto T, Murayama Y, Ogata E (1993) Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(0). Nature 362:75–79
Nitsch RM, Slack BE, Wurtman RJ, Growdon JH (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258:304–307
Nitsch RM, Farber SA, Growdon JH, Wurtman RJ (1993) Release of amyloid beta-protein precursor derivatives by electrical depolarization of rat hippocampal slices. Proc Natl Acad Sci USA 90:5191–5193
O’Neill LA, Kaltschmidt C (1997) NF-kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci 20:252–258
Okamoto T, Takeda S, Giambarella U et al. (1996) Intrinsic signaling function of APP as a novel target of three V642 mutations linked to familial Alzheimer’s disease. EMBO J 15:3769–3777
Paliga K, Peraus G, Kreger S et al. (1997) Human amyloid precursorlike protein 1 — cDNA cloning, ectopic expression in COS-7 cells and identification of soluble forms in the cerebrospinal fluid. Eur J Biochem 250:354–363
Pangalos MN, Efthimiopoulos S, Shioi J, Robakis NK (1995 a) The chondroitin sulfate attachment site of appican is formed by splicing out exon 15 of the amyloid precursor gene. J Biol Chem 270:10388–10391
Pangalos MN, Shioi J, Robakis NK (1995 b) Expression of the chondroitin sulfate proteoglycans of amyloid precursor (Appican) and amyloid precursor-like protein 2. J Neurochem 65:762–769
Paresce DM, Ghosh RN, Maxfield FR (1996) Microglial cells internalize aggregates of the Alzheimer’s disease amyloid beta-protein via a scavenger receptor. Neuron 17:553–565
Paudel HK, Lew J, Ali Z, Wang JH (1993) Brain proline-directed protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer’s paired helical filaments. J Biol Chem 268:23512–23518
Pedersen WA, Kloczewiak MA, Blusztajn JK (1996) Amyloid beta-protein reduces acetylcholine synthesis in a cell line derived from cholinergic neurons of the basal forebrain. Proc Natl Acad Sci USA 93:8068–8071
Perez RG, Zheng H, Vanderploeg LHT, Koo EH (1997) The beta-amyloid precursor protein of Alzheimer’s disease enhances neuron viability and modulates neuronal polarity. J Neurosci 17:9407–9414
Podlisny MB, Citron M, Amarante P et al. (1997) Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis 3:325–337
Polymeropoulos MH, Lavedan C, Leroy E et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047
Ponte P, Gonzalez DP, Schilling J et al. (1988) A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature 331:525–527
Poorkaj P, Bird TD, Wijsman E et al. (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–825
Querfurth HW, Selkoe DJ (1994) Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry 33:4550–4561
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
Refolo LM, Salton SR, Anderson JP, Mehta P, Robakis NK (1989) Nerve and epidermal growth factors induce the release of the Alzheimer amyloid precursor from PC 12 cell cultures. Biochem Biophys Res Commun 164:664–670
*Rogaev EI, Sherrington R, Rogaeva EA et al. (1995) 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 376:775–778
Roses AD (1996) Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med 47:387–400
*Roses AD (1998) Alzheimer diseases: A model of gene mutations and susceptibility polymorphisms for complex psychiatric diseases. Am J Med Genet 81:49–57
Rossor MN, Fox NC, Beck J, Campbell TC, Collinge J (1996) Incomplete penetrance of familial Alzheimer’s disease in a pedigree with a novel presenilin-1 gene mutation. Lancet 347:1560
*Rumble B, Retallack R, Hilbich C et al. (1989) Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s disease. N Engl J Med 320:1446–1452
Salbaum JM, Weidemann A, Lemaire HG, Masters CL, Beyreuther K (1988) The promoter of Alzheimer’s disease amyloid A4 precursor gene. EMBO J 7:2807–2813
Sandbrink R, Beyreuther K (1996) Unraveling the molecular pathway of Alzheimer’s disease: research about presenilins gathers momentum. Mol Psychiatry 1:438–444
Sandbrink R, Masters CL, Beyreuther K (1995) APP gene family: alternative splicing generates functionally related isoforms. Ann NY Acad Sci 777:281–287
Sandbrink R, Masters CL, Beyreuther K (1994 a) βA4-amyloid protein precursor mRNA isoforms without exon 15 are ubiquitously expressed in rat tissues including brain, but not in neurons. J Biol Chem 269:1510–1517
Sandbrink R, Masters CL, Beyreuther K (1994 b) Similar alternative splicing of a non-homologous domain in βA4-amyloid protein precursor-like proteins. J Biol Chem 269:14227–14234
*Sandbrink R, Hartmann T, Masters CL, Beyreuther K (1996 a) Genes contributing to lzheimer’s disease. Mol Psychiatr 1:27–40
Sandbrink R, Zhang D, Schaeffer S, Masters CL, Bauer J, Förstl H, Beyreuther K (1996 b) Missense mutations of the PS-1/S182 gene in German early-onset Alzheimer’s disease patients. Ann Neurol 40:265–266
**Scheuner D, Eckman C, Jensen M et al. (1996) Secreted amyloid β-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 2:864–870
Schmechel DE, Saunders AM, Strittmatter WJ et al. (1993) Increased amyloid β-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
Schubert D, Jin LW, Saltoh T, Cole G (1989) The regulation of amyloid beta protein precursor secretion and its modulatory role in cell adhesion. Neuron 3:689–694
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
Seeger M, Nordstedt C, Petanceska S et al. (1997) Evidence for phosphorylation and oligomeric assembly of presenilin 1. Proc Natl Acad Sci USA 94:5090–5094
*Selkoe DJ (1997) Alzheimer’s disease: genotypes, phenotypes, and treatments. Science 275:630–631
Selkoe DJ (1994) Cell biology of the amyloid β-protein precursor and the mechanism of Alzheimer’s disease. Annu Rev Cell Biol 10:373–403
*Seubert P, Vigo Pelfrey C, Esch F et al. (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359:325–327
Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S (1997) Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89:629–639
*Sherrington R, Rogaev EI, Liang Y et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375:754–760
*Shoji M, Golde TE, Ghiso J et al. (1992) Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258:126–129
Siman R, Card JP, Nelson RB, Davis LG (1989) Expression of beta-amyloid precursor protein in reactive astrocytes following neuronal damage. Neuron 3:275–285
Simons M, Ikonen E, Tienari PJ, Cidarregui A, Monning U, Beyreuther K, Dotti CG (1995) Intracellular routing of human amyloid protein precursor: Axonal delivery followed by transport to the dendrites. J Neurosci Res 41:121–128
Small DH, Nurcombe V, Reed G, Clarris H, Moir R, Beyreuther K, Masters CL (1994) A heparinbinding domain in the amyloid protein precursor of Alzheimer’s disease is involved in the regulation of neurite outgrowth. J Neurosci 14:2117–2127
Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF, Kowall N (1996) Oxidative damage in Alzheimer’s. Nature 382:120–121
Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 95:7737–7741
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840
Sprecher CA, Grant FJ, Grimm G, O’Hara PJ, Norris F, Norris K, Foster DC (1993) Molecular cloning of the cDNA for a human amyloid precursor protein homolog: evidence for a multigene family. Biochemistry 32:4481–4486
Steiner B, Mandelkow EM, Biernat J et al. (1990) Phosphorylation of microtubule-associated protein tau: identification of the site for Ca2(+)-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J 9:3539–3544
*Strittmatter WJ, Saunders AM, Schmechel D, Pericak Vance M, Enghild J, Salvesen GS, Roses AD (1993 a) Apolipoprotein E: high-avidity 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
Strittmatter WJ, Weisgraber KH, Huang D Y et al. (1993 b) Binding of human apolipoprotein E to synthetic amyloid β-peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 90:8098–8102
Strittmatter WJ, Saunders AM, Goedert M et al. (1994 a) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc Natl Acad Sci USA 91:11183–11186
Strittmatter WJ, Weisgraber KH, Goedert M et al. (1994b) Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Exp Neurol 125:163–171
Sturchlerpierrat C, Abramowski D, Duke M et al. (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94:13287–13292
*Suzuki N, Cheung TT, Cai XD et al. (1994) An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP717) mutants. Science 264:1336–1340
Tamaoka A, Sawamura N, Odaka A, Suzuki N, Mizusawa H, Shoji S, Mori H (1995) Amyloid beta protein 1–42/43 (A beta 1–42/43) in cerebellar diffuse plaques: Enzyme-linked immunosorbent assay and immunocyto chemical study. Brain Res 679:151–156
Tanzi RE, McClatchey AI, Lamperti ED, Villa KL, Gusella JF, Neve RL (1988) Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer’s disease. Nature 331:528–530
Thinakaran G, Slunt HH, Sisodia SS (1995) Novel regulation of chondroitin sulfate glycosaminoglycan modification of amyloid precursor protein and its homologue, APLP2. J Biol Chem 270:16522–16525
*Thinakaran G, Borchelt DR, Lee MK et al. (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17:181–190
Thinakaran G, Harris CL, Ratovitski T et al. (1997) Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem 272:28415–28422
Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) Beta-amyloid-mediated vaso activity and vascular endothelial damage. Nature 380:168–171
Thomas T, Sutton ET, Hellermann A, Price JM (1997) Beta-amyloid-induced coronary artery vasoactivity and endothelial damage. J Cardiovasc Pharmacol 30:517–522
Tienari PJ, Destrooper B, Ikonen E et al. (1996) The beta-amyloid domain is essential for axonal sorting of amyloid precursor protein. EMBO J 15:5218–5229
*Tienari PJ, Ida N, Ikonen E et al. (1997) Intracellular and secreted Alzheimer beta-amyloid species are generated by distinct mechanisms in cultured hippocampal neurons. Proc Natl Acad Sci USA 94:4125–4130
Trojanowski JQ, Lee VM (1995) Phosphorylation of paired helical filament tau in Alzheimer’s disease neurofibrillary lesions: focusing on phosphatases. FASEB J 9:1570–1576
Tysoe C, Whittaker J, Xuereb J et al. (1998) A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease. Am J Hum Genet 62:70–76
Ueda K, Fukushima H, Masliah E et al. (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90:11282–11286
*Van Broeckhoven C, Haan J, Bakker E et al. (1990) Amyloid β protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science 248:1120–1122
Van Gool WA, Evenhuis HM, Duijn CM van (1995) A case-control study of apolipoprotein E genotypes in Alzheimer’s disease associated with Down’s syndrome. Ann Neurol 38:225–230
Van Nostrand WE, Farrow JS, Wagner SL, Bhasin R, Goldgaber D, Cotman CW, Cunningham DD (1991) The predominant form of the amyloid beta-protein precursor in human brain is protease nexin 2. Proc Natl Acad Sci USA 88:10302–10306
Vandermeeren M, Mercken M, Vanmechelen E, Six J, Van de Voorde A, Martin JJ, Cras P (1993) Detection of tau proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem 61:1828–1834
Wallace DC, Stugard C, Murdock D, Schurr T, Brown MD (1997) Ancient mtDNA sequences in the human nuclear genome: A potential source of errors in identifying pathogenic mutations. Proc Natl Acad Sci USA 94:14900–14905
Walter J, Capell A, Grunberg J et al. (1996) The Alzheimer’s disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol Med 2:673–691
Walter J, Grunberg J, Capell A et al. (1997) Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C. Proc Natl Acad Sci USA 94:5349–5354
Wasco W, Bupp K, Magendantz M, Gusella JF, Tanzi RE, Solomon F (1992) Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor. Proc Natl Acad Sci USA 89:10758–10762
Wasco W, Gurubhagavatula S, Paradis MD et al. (1993) Isolation and characterization of APLP2 encoding a homologue of the Alzheimer’s associated amyloid β protein precursor. Nat Genet 5:95–100
Watanabe A, Hasegawa M, Suzuki M et al. (1993) In vivo phosphorylation sites in fetal and adult rat tau. J Biol Chem 268:25712–25717
*Weidemann A, Konig G, Bunke D, Fischer P, Salbaum JM, Masters CL, Beyreuther K (1989) Identification, biogenesis, localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell 57:115–126
*Weidemann A, Paliga K, Durrwang U, Czech C, Evin G, Masters CL, Beyreuther K (1997) Formation of stable complexes between two Alzheimer’s disease gene products: Presenilin-2 and beta-amyloid precursor protein. Nature Med 3:328–332
Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 72:1858–1862
Weisgraber KH, Mahley RW (1996) Human apolipoprotein E: The Alzheimer’s disease connection. FASEB J 10:1485–1494
Whitson JS, Scikoe DJ, Cotman CW (1989) Amyloid beta protein enhances the survival of hippocampal neurons in vitro. Science 243:1488–1490
Wild-Bode C, Yamazaki T, Capell A, Leimer U, Steiner H, Ihara Y, Haass C (1997) Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42. J Biol Chem 272:16085–16088
Wisniewski T, Dowjat WK, Buxbaum JD et al. (1998) A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer’s disease and leads to death as early as the age of 28 years. Neuroreport 9:217–221
Wolozin B, Iwasaki K, Vito P et al. (1996) Participation of Presenilin 2 in apoptosis: Enhanced basal activity conferred by an Alzheimer mutation. Science 274:1710–1713
Wong PC, Zheng H, Chen H et al. (1997) Presenilin 1 is required for Notchi and DII1 expression in the paraxial mesoderm. Nature 387:288–292
Wood JG, Mirra SS, Pollock NJ, Binder LI (1986) Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau). Proc Natl Acad Sci USA 83:4040–4043
Wragg M, Hutton M, Talbot C et al. (1996) Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer’s disease. Lancet 347:509–512
Xia Y, Desilva HAR, Rosi BL et al. (1996) Genetic studies in Alzheimer’s disease with an NACP/alpha-synuclein polymorphism. Ann Neurol 40:207–215
Xia WM, Zhang JM, Perez R, Koo EH, Selkoe DJ (1997) Interaction between amyloid precursor protein and presenilins in mammalian cells: Implications for the pathogenesis of Alzheimer disease. Proc Natl Acad Sci USA 94:8208–8213
Yamatsuji T, Matsui T, Okamoto T et al. (1996) G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer’s disease-associated mutants of APP. Science 272:1349–1352
Yan SD, Chen X, Fu J et al. (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691
*Yankner BA (1996) Mechanisms of neuronal degeneration in Alzheimer’s disease. Neuron 16:921–932
Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250:279–282
Yoshimoto M, Iwai A, Kang D, Otero DAC, Xia Y, Saltoh T (1995) NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proc Natl Acad Sci USA 92:9141–9145
*Younkin SG (1995) Evidence that A beta 42 is the real culprit in Alzheimer’s disease. Ann Neurol 37:287–288
Zheng H, Jiang MH, Trumbauer ME et al. (1995) beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81:525–531
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Sandbrink, R., Beyreuther, K. (1999). Molekulargenetik und Molekularbiologie der Alzheimer-Krankheit. In: Psychiatrie der Gegenwart 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60175-0_7
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