Alzheimer’s Disease: Physiological and Pathogenetic Role of the Amyloid Precursor Protein (APP), its Aβ-Amyloid Domain and Free Aβ-Amyloid Peptide
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.
KeywordsDementia Influenza Beach Neurol Fibril
Unable to display preview. Download preview PDF.
- 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: 3957–3961PubMedCrossRefGoogle Scholar
- 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: 4119–4124PubMedCrossRefGoogle Scholar
- 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: 916–919PubMedCrossRefGoogle Scholar
- 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: 1613–1620Google Scholar
- 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: 1005–1013PubMedCrossRefGoogle Scholar
- 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: 618–621Google Scholar
- 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: 67–68PubMedCrossRefGoogle Scholar
- 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: 921–923Google Scholar
- 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: 12045–12049Google Scholar
- 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: 4932–4938PubMedGoogle Scholar
- 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: 2087–2089CrossRefGoogle Scholar
- 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: 523–527PubMedCrossRefGoogle Scholar
- 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: 1550–1555PubMedCrossRefGoogle Scholar
- 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: 689–694PubMedCrossRefGoogle Scholar
- 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: 151–154Google Scholar
- 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: 1571–1577Google Scholar
- 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: 864–870PubMedCrossRefGoogle Scholar
- Sing CF, Davignon J (1985) Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Human Genet 37: 268–285Google Scholar
- 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: 13287–92CrossRefGoogle Scholar
- 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: 33556–33560Google Scholar
- 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: 735–741PubMedCrossRefGoogle Scholar
- 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: 14542–14547Google Scholar