Summary
To understand synaptic loss and neurodegeneration in Alzheimer’s disease, we have tried to consider the physiological functions of the amyloid precursor protein (APP), its Aβ-amyloid domain and of free Aβ peptide. The latter is a normal metabolic product of APP and the principal subunit of the amyloid plaques that are characteristic of Alzheimer’s disease. From studies in transgenic Drosophila melanogaster and primary mammalian neurons, we suggest that, in neurons, APP exhibits as a physiological function the negative regulation of synaptic strength whereas in nonneuronal cells APP appears to regulate cell-cell and cell-matrix adhesion.
Since the axonal transport of APP is dependent on the Aβ domain, this finding suggests that the Aβ sequence could function as an axonal sorting signal of APP. It also indicates that the Aβ region could bind to molecules that control the recruitment of APP into axonally transported vesicles.
In neurons, metabolism of APP releasing the Aβ peptide was found to occur at all sorting stations, such as at the ER/cisGolgi and TGN/endosomes producing intracellular Aβ peptide as well as at the cell surface leading to secretory Aβ peptide. Regarding the Aβ species generated in the different neuronal compartments, the long form of Aβ (Aβ42) is produced in the ER/cisGolgi and at or near the cell surface, and short Aβ (Aβ40) is produced in the TGN/endosomal compartment and also at or near the cell surface.
Given an Aβ function as an axonal sorting signal of APP, release of Aβ may regulate the axonal transport of APP. Not only does the removal of the Aβ sequence from APP abolish axonal APP transport, but also free Aβ could — by blocking the APP binding site of the axonal transport machinery of APP — serve such a regulatory, physiological function. Excess intracellular and extracellular Aβ may convert the latter physiological function of Aβ to a pathogenic one by inhibiting the axonal transport of those proteins that use the same transport system as APP.
Because the apoEε4 allele may be associated with higher cholesterol levels in neurons, and because higher risk of developing Alzheimer’s disease and axonal transport of membrane proteins are cholesterol dependent, we studied the influence of cholesterol on neuronal Aβ generation. By lowering the cholesterol level in neuronal cultures with statins (HMG-CoA reductase inhibitors), the formation of secretory and intracellular Aβ is drastically reduced. Since the amount of Aβ produced by neurons is cholesterol dependent, both the physiological and pathogenic regulation of APP transport by Aβ appears to be controled in neurons by cholesterol. This finding implies a link between brain cholesterol. APP transport, Aβ production and the risk of developing Alzheimer’s disease. These intriguing relationships open new strategies to influence the progression of Alzheimer’s disease by modulating cholesterol biosynthesis of neurons with statins.
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References
Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, Patchett A, Monaghan R, Currie S, Stapley E, Albers-Schonberg G, Hensens O, Hirshfield J, Hoogsteen K, Liesch J, Springer J (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 77: 3957–3961
Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frébourg T, Checkler F (1999) Unusual phenotypic alteration of beta amyloid precursor protein (beta APP) maturation by a new Va1715-sMet betaAPP-770 mutations responsible for probable early-onset Alzheimer disease. Proc Natl Acad Sci USA 96: 4119–4124
Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6: 916–919
Beher D, Hesse L, Master CL, Multhaup G (1996) Regulation of amyloid protein precursor ( APP) binding to collagen and mapping of the binding sites on APP and collagen type I. J Biol Chem 271: 1613–1620
Borchardt T, Camakaris J, Cappai R, Masters CL, Beyreuther K, Multhaup G (1999) Copper inhibits beta-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursorprotein secretion. Biochem J 344: 461–467.
Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovisky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate A(31–42/1–40 ratio in vitro and in vivo. Neuron 17: 1005–1013
Brown MS, Ye J, Rawson RB, Goldstein JL (2000) Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100: 391–398
Bush AI, Pettingell WJ, de Paradis M, Tanzi R, Wasco W (1994) The amyloid beta-protein precursor and its mammalian homologues. Evidence for a zinc-modulated heparin-binding superfamily. J Biol Chem 269: 618–621
Cai XD, Golde TE, Younkin SG (1993) Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science 259: 514–516
Christen Y (2000) Oxidative stress and Alzheimer disease. Am J Clin Nutr 71: 621S - 629S
Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe D (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature 360: 672–674
Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rom-mens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid (3-protein in both transfected cells and transgenic mice. Nat Med 3: 67–68
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261: 921–923
Coulson EJ, Paliga K, Beyreuther K, Masters CL (2000) What the evolution of the amyloid precursor supergene family tells us about its function. Neurochem Int 36: 175–184
Daigle I, Li C (1993) apl-1, A Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor. Proc Natl Acad Sci USA 90: 12045–12049
De Strooper B, Simons M, Multhaup G, Van Leuven F, Beyreuther K, Dotti CG (1995) Production of intracellular amyloid-containing fragments in hippocampal neurons expressing human amyloid precursor protein and protection against amyloidogenesis by subtle amino acid substitutions in the rodent sequence. EMBO J 14: 4932–4938
De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391: 387–390
Dietschy JM, Turley SD, Spady DK (1993) Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 34: 1637–1659
Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez Tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (1996) Increased amyloid(342(43) in brains of mice expressing mutant presenilin 1. Nature 383: 710–713
Eckman CB, Mehta ND, Crook R, Perez-tur J, Prihar G, Pfeifer E, Graff-Radford N, Hinder P, Yager D, Zenk B, Refolo LM, Prada CM, Younkin SG, Hutton M, Hardy J (1997) A new pathogenic mutation in the APP gene (1716V) increases the relative proportion of A beta 42(43). Human Mol Genet 6: 2087–2089
Emilien G, Beyreuther K, Masters CL, Maloteaux JM (2000) Prospects for pharmacological intervention in Alzheimer disease. Arch Neurol 57: 454–459
Fassbender K, Masters C, Beyreuther K (2000) Alzheimer’s disease: An inflammatory disease? Neurobiol Aging 21: 433–436
Fossgreen A, Bruckner B, Czech C, Masters CL, Beyreuther K, Paro R (1998) Transgenic Drosophila expressing human amyloid precursor protein show gamma-secretase activity and a blistered wing phenotype. Proc Natl Acad Sci USA 95: 13703–13708
Fuller SJ, Storey E, Li QX, Smith AI, Beyreuther K, Masters CL (1995) Intracellular production of beta A4 amyloid of Alzheimer’s disease: modulation by phosphoramidon and lack of coupling to the secretion of the amyloid precursor protein. Biochemistry 34: 8091–8098
Funato H, Enya M, Yoshimura M, Morishima-Kawashima M, Ihara Y (1999) Presence of sodium dodecyl sulfate-stable amyloid beta-protein dimers in the hippocampus CAI not exhibiting neurofibrillary tangle formation. Am J Pathol 155: 23–28
Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagopian S, Johnson-Wood K, Khan I, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, McConlogue L, Montoya Azvala 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 13-amyloid precursor protein. Nature 373: 523–527
Goedert M (1999) Filamentous nerve cell inclusions in neurogenerative diseases: tauopathies and alpha-synucleinopathies. Phil Trans R Soc Lond B Biol Sci 354: 1101–1118
Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, Parisi JE, Hyman BT (1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 41: 17–24
Grotewiel MS, Beck CD, Wu KH, Zhu XR, Davis LD (1998) Integrin-mediated short-term memory in Drosophila. Nature 391: 455–460
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
Hardy J (1994) Lewy bodies in Alzheimer’s disease in which the primary lesion is a mutation in the amyloid precursor protein. Neurosci Lett 180: 290–291
Hardy J, Gwinn-Hardy K (2000) Neurodegenerative disease: a different view of diagnosis. Mol Med Today 5: 514–517
Hartmann T, Bieger SC, Brühl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K (1997) Distinct sites of intracellular production for Alzheimer’s disease A(340/42 amyloid peptides. Nature Med 3: 1016–1020
Hilbich C, Kisters Woike B, Reed J, Masters CL, Beyreuther K (1992) Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer’s disease beta A4 peptides. J Mol Biol 228: 460–473
Hynes RO (1999) Cell adhesion: old and new questions. Trends Cell Biol 9: 33–37
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang FS, Cole G (1996) Correlative memory deficits, All elevation and amyloid plaques in transgenic mice. Science 274: 99–102
Ida N, Hartmann T, Pantel J, Schroder J, Zerfass R, Forstl H, Sandbrink R, Masters CL, Beyreuther K (1996a) Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem 271: 22908–22914
Ida N, Masters CL, Beyreuther K (1996b) Rapid cellular uptake of Alzheimer amyloid (3A4 peptide by cultured human neuroblastoma cells. FEBS Lett 394: 174–178
Ikonen E, Simons K (1998) Protein and lipid sorting from the trans-Golgi network to the plasma membrane in polarized cells. Semin Cell Dev Biol 9: 503–509
Ikonen E, Parton RG, Hunziker W, Simons K, Dotti C (1993) Transcytosis of the polymeric immunoglobin receptor in hippocampal neurons. Curr Biol 3: 635–644
Johnson-Wood K, Lee M, Motter R, Hu K, Gordon G, Barbour R, Khan K, Gordon M, Tan H, Games D, Lieberburg I, Schenk D, Seubert P, McConlogue L (1997) Amyloid precursor protein processing and A(342 deposition in a transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 94: 1550–1555
Johnstone EM, Chaney MO, Norris FH, Pascual R, Little SP (1991) Conservation of the sequence of the Alzheimer’s disease amyloid peptide in dog, polar bear and five other mammals by cross-species polymerase chain reaction analysis. Brain Res Mol Brain Res 10: 299–305
Kaether C, Skehel P, Dotti CG (2000) Axonal membrane proteins are transported in distinct carriers: a two-color video microscopy study in cultured hippocampal neurons. Mol Biol Cell 11: 1213–1224
Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Müller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325: 733–736
Koo EH, Squazzo SL (1994) Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem 269: 17386–17389
Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA 87: 1561–1565
Kwok JB, Li QX, Hallup M, Whyte S, Ames D, Beyreuther K, Masters CL, Schoffield PR (2000) Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis. Ann Neurol 47: 249–253
Lemaire HG, Salbaum JM, Multhaup G, Kang J, Bayney RM, Unterbeck A, Beyreuther K, Muller Hill B (1989) The PreA4(695) precursor protein of Alzheimer’s disease A4 amyloid is encoded by 16 exons. Nucleic Acids Res 25: 517–522
Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduveilli TG, Reguster RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell ST (2000) Photoactivated y-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405: 689–694
Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155: 853–862
Luo L, Tully T, White K (1992) Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron 9: 595–605
Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D (1996) Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F 13-amyloid precursor protein and Alzheimer’s disease. J Neurosci 16: 5795–5811
Masters CL, Beyreuther K (1998) Alzheimer’s disease. Brit Med J 316: 446–448
McLean CA, Cherry RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL (1999) Soluble pool of A(3 as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46: 860–866
Multhaup G, Bush AI, Pollwein P, Masters CL (1994) Interaction between the zine (II) and the heparin binding site of the Alzheimer’s disease beta A4 amyloid precursor protein ( APP ). FEBS Lett 355: 151–154
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
Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum J (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline JAMA 283: 1571–1577
Neufeld EB, Cooney AM, Pitha J, Dawidowicz EA, Dwyer NK, Pentchev PG, Blanchette-Mackie EJ (1996) Intracellular trafficking of cholesterol monitored with a cyclodextrin. J Biol Chem 271: 21604–21613
Niwa M, Sidrauski C, Kaufman RJ, Walter P (1999) A role for presenilin-1 in nuclear accumulation of Irel fragments and induction of the mammalian unfolded protein response. Cell 99: 691–702
Pangalos MN, Efthimiopoulos S, Shioi J, Robakis NK (1995) 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
Price DL, Sisodia SS, Borchelt DR (1998) Genetic neurodegenerative diseases: the human illness and transgenic models. Science 282: 1079–1083
Prout M, Damania Z, Soong J, Fristrom D, Fristrom JW (1997) Autosomal mutations affecting adhesion between wing surfaces in Drosophila melanogaster. Genetics 146: 275–285
Rao S, Porter DC, Chen X, Herliczek T, Lowe M, Keyomarsi K (1999) Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci USA 96: 7797–7802
Rosen DR, Martin-Morris L, Luo LQ, White K (1989) A Drosophila gene encoding a protein resembling the human beta-amyloid protein precursor. Proc Natl Acad Sci USA 86: 2478–2482
Rumble B, Retallack R, Hilbich C, Simms G, Multhaup G, Martins R, Hockey A, Montgomery P, Beyreuther K, Masters CL (1989) Amyloid A4 protein and its precursor in Down’s Syndrome and Alzheimer’s disease. N Engl J Med 320: 1446–1452
Sandbrink R, Masters CL, Beyreuther K (1994a) APP gene family• unique age-associated changes in splicing of Alzheimer’s betaA4-amyloid protein precursor. Neurobiol Dis 1: 13–24
Sandbrink R, Masters CL, Beyreuther K (1994b) Similar alternative splicing of a non-homologous domain in beta A4-amyloid protein precursor-like proteins. J Biol Chem 269: 14227–14234
Schenk DB, Seubert P, Lieberburg I, Wallace J (2000) Beta-peptide immunization: a possible new treatment for Alzheimer disease. Arch Neurol 57: 934–936
Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levey-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) Secreted amyloid n-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
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
Simons M, Ikonen E, Tienari PJ, Cid-Arregui 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
Simons M, de Strooper B, Multhaup G, Tienari PJ, Dotti CG, Beyreuther K (1996) Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons. J Neurosci 16: 899–908
Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95: 6460–6464
Sing CF, Davignon J (1985) Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Human Genet 37: 268–285
Storey E, Beyreuther K, Masters CL (1996) Alzheimer’s disease amyloid precursor protein on the surface of cortical neurons in primary culture co-localizes with adhesion patch components. Brain Res 735: 217–231
Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Nati Acad Sci USA 94: 13287–92
Suzuki N, Cheung TT, Cal XD, Odaka A, Otvos L, Eckman Jr C, Golde TE, Younkin SG (1994) An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264: 1336–1340
Taraboulos A, Scott M, Semenov A, Avrahami D, Laszlo L, Prusiner SB, Avraham D (1995) Cholesterol depletion and modification of COOH-terminal targeting sequence of the prion protein inhibit formation of the scrapie isoform. J Cell Biol 129: 121–132
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30: 572–580
Tienari PJ, De Strooper B, Ikonen E, Ida N, Simons M, Masters CL, Dotti CG, Beyreuther K (1996a) Neuronal sorting and processing of amyloid precursor protein: implications for Alzheimer’s disease. Cold Spring Harb Symp Quant Biol 61: 575–585
Tienari PJ, De Strooper B, Ikonen E, Simons M, Weidemann A, Czech C, Hartmann T, Ida N, Multhaup G, Masters CL, Van Leuven F, Beyreuther K, Dotti CG (1996b) The beta-amyloid domain is essential for axonal sorting of amyloid precursor protein. EMBO J 15: 5218–5229
Tienari PJ, Ida N, Ikonen E, Simons M, Weidemann A, Multhaup G, Masters CL, Dotti CG, Beyreuther K (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
Thinakaran G, Sisodia SS (1994) Amyloid precursor-like protein 2 (APLP2) is modified by the addition of chondroitin sulfate glycosaminoglycan at a single site. J Biol Chem 269: 22099–22104
Trommsdorff M, Borg JP, Margolis B, Herz J (1998) Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein. J Biol Chem 273: 33556–33560
Turner RS, Suzuki N, Chyung AS, Younkin SG, Lee VM (1996) Amyloids beta40 and beta42 are generated intracellularly in cultured human neurons and their secretion increases with maturation. J Biol Chem 271: 8966–8970
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286: 735–741
Vekrellis K, Ye Z, Qui WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ (2000) Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci 20: 1657–1665
Wang J, Dickson DW, Trojanowski JQ, Lee VM (1999) The levels of soluble versus insoluble brain Abeta distinguish Alzheimer’s disease from normal and pathologic aging. Exp Neurol 158: 328–337
Wolfgang WJ, Roberts IJ, Quan F, O’Kane C, Forte M (1996) Activation of protein kinase Aindependent pathways by Gs alpha in Drosophila. Proc Natl. Acad Sci USA 93: 14542–14547
Yamazaki T, Selkoe DJ, Koo EH (1995) Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons. J Cell Biol 129: 431–442
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Beyreuther, K., Masters, C.L. (2001). Alzheimer’s Disease: Physiological and Pathogenetic Role of the Amyloid Precursor Protein (APP), its Aβ-Amyloid Domain and Free Aβ-Amyloid Peptide. In: Beyreuther, K., Christen, Y., Masters, C.L. (eds) Neurodegenerative Disorders: Loss of Function Through Gain of Function. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-04399-8_7
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