Abstract
Alzheimer’s disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39–42 residues known as amyloid beta-peptide (Aβ) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Aβ precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Aβ deposition. Several biochemical and molecular studies using transfected cells and transgenic animals point to mechanisms by which Aβ is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as “secretases” participate in APP processing. An enzymatic activity, β-secretase, cleaves APP on the amino side of Aβ producing a large secreted derivative, sAPPβ, and an Aβ-bearing membrane-associated C-terminal derivative, CTFβ, which is subsequently cleaved by the second activity, γ-secretase, to release Aβ. Alternatively, a third activity, α-secretase, cleaves APP within Aβ to the secreted derivative sAPPα and membrane-associated CTFα. The predominant secreted APP derivative is sAPPα in most cell-types. Most of the secreted Aβ is 40 residues long (Aβ40) although a small percentage is 42 residues in length (Aβ42). However, the longer Aβ42 aggregates more readily and was therefore considered to be the pathologically important form. Advances in our understanding of APP processing, trafficking, and turnover will pave the way for better drug discovery for the eventual treatment of AD. In addition, APP gene regulation and its interaction with other proteins may provide useful drug targets for AD. The emerging knowledge related to the normal function of APP will help in determining whether or not the AD associated changes in APP metabolism affect its function. The present review summarizes our current understanding of APP metabolism and function and their relationship to other proteins involved in AD.
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Abbenante G., Kovacs D. M., Leung D. L., Craik D. J., Tanzi R. E., and Fairlie D. P. (2000) Inhibitors of β-amyloid formation based on the β-secretase cleavage site. Biochem. Biophys. Res. Commun. 268, 133–135.
Abraham C. R., McGraw W. T., Slot F., and Yamin R. (2000) Alpha 1-antichymotrypsin inhibits A beta degradation in vitro and in vivo. Ann. NY Acad. Sci. 920, 245–248.
Adler M. J., Coronel C., Shelton E., Seegmiller J. E., and Dewji N. N. (1991) Increased gene expression of Alzheimer disease beta-amyloid precursor protein in senescent cultured fibroblasts. Proc. Natl. Acad. Sci. USA 88, 16–20.
Akiyama H., Barger S., Barnum S., Bradt B., Bauer J., Cole G. M., et al. (2000) Inflammation and Alzheimer’s disease. Neurobiol. Aging 21, 383–421.
Anderson J. P., Esch F. S., Keim P. S., Sambamurti K., Lieberburg I., and Robakis N. K. (1991) Exact cleavage site of Alzheimer amyloid precursor in neuronal PC-12 cells. Neurosci. Lett. 128, 126–128.
Ando K., Iijima Ki K., Elliott J. I., Kirino Y., and Suzuki T. (2001) Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid. J. Biol. Chem. 21, 21.
Ariga T., Kobayashi K., Hasegawa A., Kiso M., Ishida H., and Miyatake T. (2001) Characterization of high-affinity binding between gangliosides and amyloid beta-protein. Arch. Biochem. Biophys. 388, 225–230.
Arribas J., Coodly L., Vollmer P., Kishimoto T. K., Rose-John S., and Massague J. (1996) Diverse cell surface protein ectodomains are shed by a system sensitive to metalloprotease inhibitors. J. Biol. Chem. 271, 11,376–11,382.
Baki L., Marambaud P., Efthimiopoulos S., Georgakopoulos A., Wen P., Cui W., et al. (2001) Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex. Proc. Natl. Acad. Sci. USA 98, 2381–2386.
Bales K. R., Verina T., Dodel R. C., Du Y., Altstiel L., Bender M., et al. (1997) Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nature Genet. 17. 263–264.
Bartus R. T., Dean R. L. 3rd, Beer B., and Lippa A. S. (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408–414.
Beffert U. and Poirier J. (1996) Apolipoprotein E, plaques, tangles and cholinergic dysfunction in Alzheimer’s disease. Ann. NY Acad. Sci. 777, 166–174.
Benjannet S., Elagoz A., Wickham L., Mamarbachi M., Munzer J. S., Basak A., et al. (2001) Posttranslational processing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-beta production. J. Biol. Chem. 276, 10,879–10,887.
Bennett B. D., Denis P., Haniu M., Teplow D. B., Kahn S., Louis J. C., et al. (2000) A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’s beta-secretase. J. Biol. Chem. 275, 37,712–37,717.
Black R. A., Rauch C. T., Kozlosky C. J., Peschon J. J., Slack J. L., Wolfson M. F., et al. (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385, 729–733.
Blacker D., Wilcox M. A., Laird N. M., Rodes L., Horvath S. M., Go R. C., et al. (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat. Genet. 19, 357–360.
Borg J. P., Ooi J., Levy E., and Margolis B. (1996) The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. Mol. Cell. Biol. 16, 6229–6241.
Borg J. P., Yang Y., De Taddeo-Borg M., Margolis B., and Turner R. S. (1998) The X11 alpha protein slows cellular amyloid precursor protein processing and reduces Abeta40 and Abeta42 secretion. J. Biol. Chem. 273, 14,761–14,766.
Bressler S. L., Gray M. D., Sopher B. L., Hu Q., Hearn M. G., Pham D. G., et al. (1996) cDNA cloning and chromosome mapping of the human Fe65 gene: interaction of the conserved cytoplasmic domains of the human beta-amyloid precursor protein and its homologues with the mouse Fe65 protein. Hum. Mol. Genet. 5, 1589–1598.
Brion J. P., Nunez J., and Flament Durand J. (1985) Immunological detection of Tau protein in neurofibrillary tangles of Alzheimer’s disease. Arch. Biol. 96, 229–235.
Brouillet E., Trembleau A., Galanaud D., Volovitch M., Bouillot C., Valenza C., et al. (1999) The amyloid precursor protein interacts with Go heterotrimeric protein within a cell compartment specialized in signal transduction. J. Neurosci. 19, 1717–1727.
Brown D. (1994) GPI-anchored proteins and detergent-resistant membrane domains. Braz. J. Med. Biol. Res. 27, 309–315.
Burns A., Tomlinson B. E., and Mann D. M. (1997) Observations on the brains of demented old people. B. E. Tomlinson, G. Blessed and M. Roth, J. Neurol. Sci. (1970) 11, 205–242 and Observations on the brains of non-demented old people. B. E. Tomlinson, G. Blessed and M. Roth, J. Neurol. Sci. (1968) 7, 331–356. Int. J. Geriatr. Psychiatry 12, 785–790.
Buxbaum J. D., Gandy S. E., Cicchetti P., Ehrlich M. E., Czernik A. J., Fracasso R. 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 J. D., Oishi M., Chen H. I., Pinkas-Kramarski R., Jaffe E. A., Gandy S. E., and Greengard P. (1992) Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proc. Natl. Acad. Sci. USA 89, 10,075–10,078.
Buxbaum J. D., Koo E. H., and Greengard P. (1993) Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide. Proc. Natl. Acad. Sci. USA 90, 9195–9198.
Buxbaum J. D., Ruefli A. A., Parker C. A., Cypess A. M., and 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.
Buxbaum J. D., Liu K. N., Luo Y., Slack J. L., Stocking K. L., Peschon J. J., et al. (1998) Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273, 27,765–27,767.
Cai H., Wang Y., McCarthy D., Wen H., Borchelt D. R., Price D. L., and Wong P. C. (2001) BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nature Neurosci. 4, 233–234.
Cao X. and Sudhof T. C. (2001) A transcriptively active complex of APP with Fe65 and histone acetyl-transferase Tip60. Science 293, 115–120.
Capell A., Grunberg J., Pesold B., Diehlmann A., Citron M., Nixon R., 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.
Chae H. S., Bach J. H., Lee M. W., Kim H. S., Kim Y. S., Kim K. Y., et al. (2001) Estrogen attenuates cell death induced by carboxy-terminal fragment of amyloid precursor protein in PC12 through a receptor-dependent pathway. J. Neurosci. Res. 65, 403–407.
Checler F. (1995) Processing of the beta-amyloid precursor protein and its regulation in Alzheimer’s disease. J. Neurochem. 65, 1431–1444.
Chen F., Yang D. S., Petanceska S., Yang A., Tandon A., Yu G., et al. (2000) Carboxyl-terminal fragments of Alzheimer beta-amyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells. J. Biol. Chem. 275, 36,794–36,802.
Chow N., Korenberg J. R., Chen X. N., and Neve R. L. (1996) APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein. J. Biol. Chem. 271, 11,339–11,346.
Citron M., Diehl T. S., Capell A., Haass C., Teplow D. B., and Selkoe D. J. (1996) Inhibition of amyloid beta-protein production in neural cells by the serine protease inhibitor AEBSF. Neuron 17, 171–179.
Citron M., Westaway D., Xia W., Carlson G., Diehl T., Levesque G., et al. (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature Med. 3, 67–72.
Clark L. N., Poorkaj P., Wszolek Z., Geschwind D. H., Nasreddine Z. S., Miller B., et al. (1998) Pathogenic implications of mutations in the tau gene in pallidoponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc. Natl. Acad. Sci. USA 95, 13,103–13,107.
Clarris H. J., Cappai R., Heffernan D., Beyreuther K., Masters C. L., and Small D. H. (1997) Identification of heparin-binding domains in the amyloid precursor protein of Alzheimer’s disease by deletion mutagenesis and peptide mapping. J. Neurochem. 68, 1164–1172.
Condon T. P., Flournoy S., Sawyer G. J., Baker B. F., Kishimoto T. K., and Bennett C. F. (2001) ADAM17 but not ADAM10 mediates tumor necrosis factor-alpha and L-selectin shedding from leukocyte membranes. Antisense Nucleic Acid Drug Dev. 11, 107–116.
Coughlan C. M. and Breen K. C. (2000) Factors influencing the processing and function of the amyloid beta precursor protein—a potential therapeutic target in Alzheimer’s disease? Pharmacol. Ther. 86, 111–145.
Creemers J. W., Ines Dominguez D., Plets E., Serneels L., Taylor N. A., Multhaup G., et al. (2001) Processing of beta-secretase by furin and other members of the proprotein convertase family. J. Biol. Chem. 276, 4211–4217.
Cupers P., Bentahir M., Craessaerts K., Orlans I., Vanderstichele H., Saftig P., et al. (2001a). The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein. J. Cell. Biol. 154, 731–740.
Cupers P., Orlans I., Craessaerts K., Annaert W., and De Strooper B. (2001b) The amyloid precursor protein (APP)-cytoplasmic fragment generated by gamma-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture. J. Neurochem. 78, 1168–1178.
Daigle I. and 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, 12,045–12,049.
Davies P. and Maloney A. J. (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2, 1403.
De Strooper B., Umans L., Van Leuven F., and Van Den Berghe H. (1993) Study of the synthesis and secretion of normal and artificial mutants of murine amyloid precursor protein (APP): cleavage of APP occurs in a late compartment of the default secretion pathway. J. Cell Biol. 121, 295–304.
De Strooper B., Saftig P., Craessaerts K., Vanderstichele H., Guhde G., Annaert W., et al. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390.
De Strooper B., Annaert W., Cupers P., Saftig P., Craessaerts K., Mumm J. S., et al. (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522.
De Strooper B. and Annaert W. (2000) Proteolytic processing and cell biological functions of the amyloid precursor protein. J. Cell Sci. 113, 1857–1870.
Doan A., Thinakaran G., Borchelt D. R., Slunt H. H., Ratovitsky T., Podlisny M., et al. (1996) Protein topology of presenilin 1. Neuron 17, 1023–1030.
Duff K., Eckman C., Zehr C., Yu X., Prada C. M., Pereztur J., et al. (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713.
Duilio A., Zambrano N., Mogavero A. R., Ammendola R., Cimino F., and Russo T. (1991) A rat brain mRNA encoding a transcriptional activator homologous to the DNA binding domain of retroviral integrases. Nucleic Acids Res. 19, 5269–5274.
Eckman E. A., Reed D. K., and Eckman C. B. (2001) Degradation of the Alzheimer’s amyloid beta peptide by endothelin-converting enzyme. J. Biol. Chem. 276, 24,540–24,548.
Ermekova K. S., Zambrano N., Linn H., Minopoli G., Gertler F., Russo T., and Sudol M. (1997) The WW domain of neural protein FE65 interacts with proline-rich motifs in Mena, the mammalian homolog of Drosophila enabled. J. Biol. Chem. 272, 32,869–32,877.
Esch F. S., Keim P. S., Beattie E. C., Blacher R. W., Culwell A. R., Oltersdorf T., et al. (1990) Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 248, 1122–1124.
Esler W. P., Kimberly W. T., Ostaszewski B. L., Diehl T. S., Moore C. L., Tsai J. Y., et al. (2000) Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nature Cell Biol. 2, 428–434.
Estus S., Golde T. E., Kunishita T., Blades D., Lowery D., Eisen M., et al. (1992) Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science 255, 726–728.
Farzan M., Schnitzler C. E., Vasilieva N., Leung D., and Choe H. (2000) BACE2, a beta-secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc. Natl. Acad. Sci. USA 97, 9712–9717.
Fassbender K., Simons M., Bergmann C., Stroick M., Lutjohann D., Keller P., et al. (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc. Natl. Acad. Sci. USA 98, 5856–5861.
Figueiredo-Pereira M. E., Efthimiopoulos S., Tezapsidis N., Buku A., Ghiso J., Mehta P., and Robakis N. K. (1999) Distinct secretases, a cysteine protease and a serine protease, generate the C termini of amyloid beta-proteins Abeta 1–40 and Abeta 1–42, respectively. J. Neurochem. 72, 1417–1422.
Fillit H., Weinreb H., Cholst I., Luine V., McEwen B., Amador R., and Zabriskie J. (1986) Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer’s type. Psychoneuroendocrinology 11, 337–345.
Fiore F., Zambrano N., Minopoli G., Donini V., Duilio A., and Russo T. (1995) The regions of the Fe65 protein homologous to the phosphotyrosine interaction/phosphotyrosine binding domain of Shc bind the intracellular domain of the Alzheimer’s amyloid precursor protein. J. Biol. Chem. 270, 30,853–30,856.
Fossgreen A., Bruckner B., Czech C., Masters C. L., Beyreuther K., and 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, 13,703–13,708.
Fox N. W., Johnstone E. M., Ward K. E., Schrementi J., and Little S. P. (1997) APP gene promoter constructs are preferentially expressed in the CNS and testis of transgenic mice. Biochem. Biophys. Res. Commun. 240, 759–762.
Frears E. R., Stephens D. J., Walters C. E., Davies H., and Austen B. M. (1999) The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport 10, 1699–1705.
Gabuzda D., Busciglio J., and Yankner B. A. (1993) Inhibition of beta-amyloid production by activation of protein kinase C. J. Neurochem. 61, 2326–2329.
Gertler F. B., Niebuhr K., Reinhard M., Wehland J., and Soriano P. (1996) Mena, a relative of VASP and Drosophila Enabled, is implicated in the control of microfilament dynamics. Cell 87, 227–239.
Ghiso J., Rostagno A., Gardella J. E., Liem L., Gorevic P. D., and Frangione B. (1992) A 109-amino-acid C-terminal fragment of Alzheimer’s-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell adhesion. Biochemical. J. 288, 1053–1059.
Giacobini E. (1998) Cholinergic foundations of Alzheimer’s disease therapy. J. Physiol. Paris 92, 283–287.
Glenner G. G. and Wong C. W. (1984a) Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. 122, 1131–1135.
Glenner G. G. and Wong C. W. (1984b) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890.
Glenner G. G., Wong C. W., Quaranta V., and Eanes E. D. (1984) The amyloid deposits in Alzheimer’s disease: their nature and pathogenesis. Appl. Pathol. 2, 357–369.
Goldgaber D., Lerman M. I., McBride O. W., Saffiotti U., and Gajdusek D. C. (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science 235, 877–880.
Goldgaber D., Harris H. W., Hla T., Maciag T., Donnelly R. J., Jacobsen J. S., et al. (1989) Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. Proc. Natl. Acad. Sci. USA 86, 7606–7610.
Gotz J., Chen F., van Dorpe J., and Nitsch R. M. (2001) Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491–1495.
Gouras G. K., Xu H., Jovanovic J. N., Buxbaum J. D., Wang R., Greengard P., et al. (1998) Generation and regulation of beta-amyloid peptide variants by neurons. J. Neurochem. 71, 1920–1925.
Grundke-Iqbal I., Wang G. P., Iqbal K., Tung Y. C., and Wisniewski H. M. (1985) Alzheimer paired helical filaments: identification of polypeptides with monoclonal antibodies. Acta Neuropathol. 68, 279–283.
Grundke-Iqbal I., Iqbal K., Quinlan M., Tung Y. C., Zaidi M. S., and Wisniewski H. M. (1986) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261, 6084–6089.
Gu Y., Misonou H., Sato T., Dohmae N., Takio K., and Ihara Y. (2001) Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch. J. Biol. Chem. in press.
Guenette S. Y., Chen J., Jondro P. D., and Tanzi R. E. (1996) Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein. Proc. Natl. Acad. Sci. USA 93, 10,832–10,837.
Guenette S. Y., Chen J., Ferland A., Haass C., Capell A., and Tanzi R. E. (1999) hFE65L influences amyloid precursor protein maturation and secretion. J. Neurochem. 73, 985–993.
Haas C., Aldudo J., Cazorla P., Bullido M. J., de Miguel C., Vazquez J., and Valdivieso F. (1997) Proteolysis of Alzheimer’s disease beta-amyloid precursor protein by factor Xa. Biochim. Biophys. Acta 1343, 85–94.
Haass C., Hung A. Y., and Selkoe D. J. (1991) Processing of beta-amyloid precursor protein in microglia and astrocytes favors an internal localization over constitutive secretion. J. Neurosci. 11, 3783–3793.
Haass C., Hung A. Y., Schlossmacher M. G., Teplow D. B., and Selkoe D. J. (1993) Beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J. Biol. Chem. 268, 3021–3024.
Haugabook S. J., Le T., Yager D., Zenk B., Healy B. M., Eckman E. A., et al. (2001) Reduction of Abeta accumulation in the Tg2576 animal model of Alzheimer’s disease after oral administration of the phosphatidyl-inositol kinase inhibitor wortmannin. FASEB J. 15, 16–18.
Halverson K., Fraser P. E., Kirschner D. A., and Lansbury P. T. Jr. (1990) Molecular determinants of amyloid deposition in Alzheimer’s disease: conformational studies of synthetic beta-protein fragments. Biochemistry 29, 2639–2644.
Hardy J. (1992) Framing beta-amyloid. Nature Genet. 1, 233–234.
Hardy J. and Gwinn-Hardy K. (1998) Genetic classification of primary neurodegenerative disease. Science 282, 1075–1079.
Hashimoto Y., Jiang H., Niikura T., Ito Y., Hagiwara A., Umezawa K., et al. (2000) Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases. J. Neurosci. 20, 8401–8409.
Hattori M., Tsukahara F., Furuhata Y., Tanahashi H., Hirose M., Saito M., et al. (1997) A novel method for making nested deletions and its application for sequencing of a 300 kb region of human APP locus. Nucleic Acids Res. 25, 1802–1808.
Heber S., Herms J., Gajic V., Hainfellner J., Aguzzi A., Rulicke T., et al. (2000) Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J. Neurosci. 20, 7951–7963.
Herreman A., Serneels L., Annaert W., Collen D., Schoonjans L., and De Strooper B. (2000) Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nature Cell Biol. 2, 461–462.
Holton J. L., Ghiso J., Lashley T., Rostagno A., Guerin C. J., Gibb G., et al. (2001) Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia. Am. J. Pathol. 158, 515–526.
Homayouni R., Rice D. S., Sheldon M., and Curran T. (1999) Disabled-1 binds to the cytoplasmic domain of amyloid precursor-like protein 1. J. Neurosci. 19, 7507–7515.
Hong M., Zhukareva V., Vogelsberg-Ragaglia V., Wszolek Z., Reed L., Miller B. I., et al. (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914–1917.
Howell B. W., Lanier L. M., Frank R., Gertler F. B., and Cooper J. A. (1999) The disabled 1 phosphotyrosine-binding domain binds to the internalization signals of transmembrane glycoproteins and to phospholipids. Mol. Cell Biol. 19, 5179–5188.
Hsiao K., Chapman P., Nilsen S., Eckman C., Harigaya Y., Younkin S., et al. (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99–102.
Hung A. Y. and Selkoe D. J. (1994) Selective ectodomain phosphorylation and regulated cleavage of beta-amyloid precursor protein. EMBO J. 13, 534–542.
Hussain I., Powell D., Howlett D. R., Tew D. G., Meek T. D., Chapman C., et al. (1999) Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol. Cell Neurosci. 14, 419–427.
Hutton M., Lendon C. L., Rizzu P., Baker M., Froelich S., Houlden H., et al. (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705.
Igbavboa U., Avdulov N. A., Chochina S. V., and Wood W. G. (1997) Transbilayer distribution of cholesterol is modified in brain synaptic plasma membranes of knockout mice deficient in the low-density lipoprotein receptor, apolipoprotein E, or both proteins. J. Neurochem. 69, 1661–1667.
Ikezu T., Trapp B. D., Song K. S., Schlegel A., Lisanti M. P., and Okamoto T. (1998) Caveolae, plasma membrane microdomains for alpha-secretase-mediated processing of the amyloid precursor protein. J. Biol. Chem. 273, 10,485–10,495.
Iwata N., Tsubuki S., Takaki Y., Watanabe K., Sekiguchi M., Hosoki E., et al. (2000) Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nature Med. 6, 143–150.
Iwata N., Tsubuki S., Takaki Y., Shirotani K., Lu B., Gerard N. P., et al. (2001) Metabolic regulation of brain Abeta by neprilysin. Science 292, 1550–1552.
Izumi Y., Hirata M., Hasuwa H., Iwamoto R., Umata T., Miyado K., et al. (1998) A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 17, 7260–7272.
Jaffe A. B., Toran-Allerand C. D., Greengard P., and Gandy S. E. (1994) Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J. Biol. Chem. 269, 13,065–13,068.
Joachim C. L., Morris J. H., Kosik K. S., and Selkoe D. J. (1987a) Tau antisera recognize neurofibrillary tangles in a range of neurodegenerative disorders. Ann. Neurol. 22, 514–520.
Joachim C. L., Morris J. H., Selkoe D. J., and Kosik K. S. (1987b) Tau epitopes are incorporated into a range of lesions in Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 46, 611–622.
John V., Latimer L. H., Tung J. S., and Dappen M. S. (1997) Alzheimer’s Disease: Recent Advances on the Amyloid Hypothesis. Annual Reports in Medicinal Chemistry, Vol. 32, Academic Press, San Diego, pp. 12–20.
Johnson S. A., McNeill T., Cordell B., and Finch C. E. (1990) Relation of neuronal APP-751/APP-695 mRNA ratio and neuritic plaque density in Alzheimer’s disease. Science 248, 854–857.
Johnston J. A., Norgren S., Ravid R., Wasco W., Winblad B., Lannfelt L., and Cowburn R. F. (1996) Quantification of APP and APLP2 mRNA in APOE genotyped Alzheimer’s disease brains. Brain Res. Mol. Brain Res. 43, 85–95.
Kakio A., Nishimoto S. I., Yanagisawa K., Kozutsumi Y., and Matsuzaki K. (2001) Cholesterol-dependent formation of GM1 ganglioside-bound amyloid beta-protein, an endogenous seed for Alzheimer amyloid. J. Biol. Chem. 276, 24,985–24,990.
Kang J., Lemaire H. G., Unterbeck A., Salbaum J. M., Masters C. L., Grzeschik K. H., et al. (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736.
Kim S. J., Park K., Rudkin B. B., Dey B. R., Sporn M. B., and Roberts A. B. (1994) Nerve growth factor induces transcription of transforming growth factor-beta 1 through a specific promoter element in PC12 cells. J. Biol. Chem. 269, 3739–3744.
Kimberly W. T., Xia W., Rahmati T., Wolfe M. S., and Selkoe D. J. (2000) The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. J. Biol. Chem. 275, 3173–3178.
Kimberly W. T., Zheng J. B., Guenette S., and Selkoe D. J. (2001) The intracellular domain of the β-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a Notch-like manner. J. Biol. Chem., in press.
Klafki H., Abramowski D., Swoboda R., Paganetti P. A., and Staufenbiel M. (1996) The carboxyl termini of beta-amyloid peptides 1–40 and 1–42 are generated by distinct gamma-secretase activities. J. Biol. Chem. 271, 28,655–28,659.
Knops J., Gandy S., Greengard P., Lieberburg I., and Sinha S. (1993) Serine phosphorylation of the secreted extracellular domain of APP. Biochem. Biophys. Res. Commun. 197, 380–385.
Koike H., Tomioka S., Sorimachi H., Saido T. C., Maruyama K., Okuyama A., et al. (1999) Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein. Biochem. J. 343, 371–375.
Kojro E., Gimpl G., Lammich S., Marz W., and Fahrenholz F. (2001) Low cholesterol stimulates the non-amyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc. Natl. Acad. Sci. USA 98, 5815–5820.
Komano H. and Fuller R. S. (1995) Shared functions in vivo of a glycosyl-phosphatidylinositol-linked aspartyl protease, Mkc7, and the proprotein processing protease Kex2 in yeast. Proc. Natl. Acad. Sci. USA 92, 10,752–10,756.
Koo E. H. and Squazzo S. L. (1994) Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J. Biol. Chem. 269, 17,386–17,389.
Kosik K. S., Joachim C. L., and Selkoe D. J. (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.
Kuentzel S. L., Ali S. M., Altman R. A., Greenberg B. D., and Raub T. J. (1993) The Alzheimer beta-amyloid protein precursor/protease nexin-II is cleaved by secretase in a trans-Golgi secretory compartment in human neuroglioma cells. Biochem J. 295, 367–378.
Lahiri D. K. and Robakis N. K. (1991) The promoter activity of the gene encoding Alzheimer beta-amyloid precursor protein (APP) is regulated by two blocks of upstream sequences. Brain Res. Mol. Brain Res. 9, 253–257.
Lahiri D. K., Lewis S., and Farlow M. R. (1994) Tacrine alters the secretion of the beta-amyloid precursor protein in cell lines. J. Neurosci. Res. 37, 777–787.
Lahiri D. K. and Nall C. (1995) Promoter activity of the gene encoding the beta-amyloid precursor protein is up-regulated by growth factors, phorbol ester, retinoic acid and interleukin-1. Brain Res. Mol. Brain Res. 32, 233–240.
Lahiri D. K., Farlow M. R., and Sambamurti K. (1998) The secretion of amyloid beta-peptides is inhibited in the tacrine-treated human neuroblastoma cells. Brain Res. Mol. Brain Res. 62, 131–140.
Lahiri D. K. and Sambamurti K. (2000) Neurodiagnostics: Focus on Alzheimer’s Disease. Spectrum Diagnost. Rel. Technol. 10, 1–14. (A publication of Decision Resources: sama.dresources.com)
Lahiri D. K., Farlow M. R., Hintz N., Utsuki T., and Grieg N. H. (2001) Cholinesterase inhibitors, beta-amyloid precursor protein and amyloid beta-peptides in Alzheimer’s disease. Acta Neurol. Scand. 176, 60–67.
Lambert J. C., Goumidi L., Vrieze F. W., Frigard B., Harris J. M., Cummings A., et al. (2000) The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer’s disease. Hum. Mol. Genet. 9, 2275–2280.
Lammich S., Kojro E., Postina R., Gilbert S., Pfeiffer R., Jasionowski M., et al. (1999) Constitutive and regulated alpha secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl. Acad. Sci. USA 96, 3922–3927.
LeBlanc A. (1995) Increased production of 4 kDa amyloid beta peptide in serum deprived human primary neuron cultures: possible involvement of apoptosis. J. Neurosci. 15, 7837–7846.
LeBlanc A. C., Liu H., Goodyer C., Bergeron C., and Hammond J. (1999) Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer’s disease. J. Biol. Chem. 274, 23,426–23,436.
LeBlanc A. C., Papadopoulos M., Belair C., Chu W., Crosato M., Powell J., and Goodyer C. G. (1997) Processing of amyloid precursor protein in human primary neuron and astrocyte cultures. J. Neurochem. 68, 1183–1190.
LeBlanc A. C. and Goodyer C. G. (1999) Role of endoplasmic reticulum, endosomal-lysosomal compartments, and microtubules in amyloid precursor protein metabolism of human neurons. J. Neurochem. 72, 1832–1842.
Ledesma M. D., Da Silva J. S., Crassaerts K., Delacourte A., De Strooper B., and Dotti C. G. (2000) Brain plasmin enhances APP alpha-cleavage and Abeta degradation and is reduced in Alzheimer’s disease brains. EMBO Rep. 1, 530–535.
Lee S. J., Liyanage U., Bickel P. E., Xia W., Lansbury P. T. Jr., and Kosik K. S. (1998) A detergent-insoluble membrane compartment contains Abeta in vivo. Nature Med. 4, 730–734.
Lemere C. A., Lopera F., Kosik K. S., Lendon C. L., Ossa J., Saido T. C., et al. (1996) The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nature Med. 2, 1146–1150.
Leveugle B., Ding W., Durkin J. T., Mistretta S., Eisle J., Matic M., et al. (1997) Heparin promotes beta-secretase cleavage of the Alzheimer’s amyloid precursor protein. Neurochem Int. 30, 543–548.
Levitan D., Doyle T. G., Brousseau D., Lee M. K., Thinakaran G., Slunt H. H., et al. (1996) Assessment of normal and mutant human presenilin found in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 93, 14,940–14,944.
Levy-Lahad E., Wasco W., Poorkaj P., Romano D. M., Oshima J., Pettingell W. H., et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977.
Lewis J., McGowan E., Rockwood J., Melrose H., Nacharaju P., Van Slegtenhorst M., et al. (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genet. 25, 402–405.
Lewis J., Dickson D. W., Lin W. L., Chisholm L., Corral A., Jones G., et al. (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491.
Li X. and Greenwald I. (1998) Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins. Proc. Natl. Acad. Sci. USA 95, 7109–7114.
Li Y. M., Lai M. T., Xu M., Huang Q., DiMuzio-Mower J., Sardana M. K., et al. (2000a) Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc. Natl. Acad. Sci. USA 97, 6138–6143.
Li Y. M., Xu M., Lai M. T., Huang Q., Castro J. L., DiMuzio-Mower J., et al. (2000b) Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405, 689–694.
Lin X., Koelsch G., Wu S., Downs D., Dashti A., and Tang J. (2000) Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc. Natl. Acad. Sci. USA 97, 1456–1460.
Lisanti M. P., Tang Z., Scherer P. E., Kubler E., Koleske A. J., and Sargiacomo M. (1995) Caveolae, transmembrane signalling and cellular transformation. Mol. Membr. Biol. 12, 121–124.
Lopez-Perez E., Seidah N. G., and Checler F. (1999) Proprotein convertase activity contributes to the processing of the Alzheimer’s beta-amyloid precursor protein in human cells: evidence for a role of the prohormone convertase PC7 in the constitutive alpha- secretase pathway. J. Neurochem. 73, 2056–2062.
Lopez-Perez E., Zhang Y., Frank S. J., Creemers J., Seidah N., and Checler F. (2001) Constitutive alpha-secretase cleavage of the beta-amyloid precursor protein in the furin-deficient Lo Vo cell line: involvement of the pro-hormone convertase 7 and the disintegrin metalloprotease ADAM10. J. Neurochem. 76, 1532–1539.
Lorenzo A. and Yankner B. A. (1994) Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc. Natl. Acad. Sci. USA 91, 12,243–12,247.
Lu D. C., Rabizadeh S., Chandra S., Shayya R. F., Ellerby L. M., Ye X., et al. (2000) A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor. Nature Med. 6, 397–404.
Luc P. V. and Wagner J. A. (1997) Regulation of the neural-specific gene VGF in PC12 cells. Identification of transcription factors interacting with NGF-responsive elements. J. Mol. Neurosci. 8, 223–241.
Luo L., Tully T., and White K. (1992) Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron 9, 595–605.
Luo L. Q., Martin-Morris L. E., and White K. (1990) Identification, secretion, and neural expression of APPL, a Drosophila protein similar to human amyloid protein precursor. J. Neurosci. 10, 3849–3861.
Luo Y., Bolon B., Kahn S., Bennett B. D., Babu-Khan S., Denis P., et al. (2001) Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nature Neurosci. 4, 231–232.
Martin-Morris L. E. and White K. (1990) The Drosophila transcript encoded by the beta-amyloid protein precursor-like gene is restricted to the nervous system. Development 110, 185–195.
Masters C. L., Simms G., Weinman N. A., Multhaup G., McDonald B. L., and Beyreuther K. (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. USA 82, 4245–4249.
Matsuda S., Yasukawa T., Homma Y., Ito Y., Niikura T., Hiraki T., et al. (2001) c-Jun n-terminal kinase (jnk)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer’s amyloid precursor protein with jnk. J. Neurosci. 21, 6597–6607.
Mattson M. P., Barger S. W., Furukawa K., Bruce A. J., Wyss-Coray T., Mark R. J., and Mucke L. (1997) Cellular signaling roles of TGF beta, TNF alpha and beta APP in brain injury responses and Alzheimer’s disease. Brain Res. Brain Res. Rev. 23, 47–61.
McLendon C., Xin T., Ziani-Cherif C., Murphy M. P., Findlay K. A., Lewis P. A., et al. (2000) Cell-free assays for gamma-secretase activity. FASEB J. 14, 2383–2386.
McLoughlin D. M. and Miller C. C. (1996) The intracellular cytoplasmic domain of the Alzheimer’s disease amyloid precursor protein interacts with phosphotyrosine-binding domain proteins in the yeast two-hybrid system. FEBS Lett. 397, 197–200.
Mills J. and Reiner P. B. (1999) Regulation of amyloid precursor protein cleavage. J. Neurochem. 72, 443–460.
Minopoli G., de Candia P., Bonetti A., Faraonio R., Zambrano N., and Russo T. (2001) The beta-amyloid precursor protein functions as a cytosolic anchoring site that prevents Fe65 nuclear translocation. J. Biol. Chem. 276, 6545–6550.
Mori T., Paris D., Town T., Rojiani A. M., Sparks D. L., Delledonne A., et al. (2001) Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice. J. Neuropathol. Exp. Neurol. 60, 778–785.
Morishima-Kawashima M. and Ihara Y. (1998) The presence of amyloid beta-protein in the detergent-insoluble membrane compartment of human neuroblastoma cells. Biochemistry 37, 15,247–15,253.
Moss M. L., Jin S. L., Becherer J. D., Bickett D. M., Burkhart W., Chen W. J., et al. (1997a) Structural features and biochemical properties of TNF-alpha converting enzyme (TACE). J. Neuroimmunol. 72, 127–129.
Moss M. L., Jin S. L., Milla M. E., Bickett D. M., Burkhart W., Carter H. L., et al. (1997b) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385, 733–736.
Mueller H. T., Borg J. P., Margolis B., and Turner R. S. (2000) Modulation of amyloid precursor protein metabolism by X11-alpha/Mint-1. A deletion analysis of protein-protein interaction domains. J. Biol. Chem. 275, 39,302–39,306.
Myers A. J. and Goate A. M. (2001) The genetics of late-onset Alzheimer’s disease. Curr. Opin. Neurol. 14, 433–440.
Narita M., Holtzman D. M., Schwartz A. L., and Bu G. (1997) Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein. J. Neurochem. 69, 1904–1911.
Nilsberth C., Westlind-Danielsson A., Eckman C. B., Condron M. M., Axelman K., Forsell C., et al. (2001). The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nature Neurosci. 4, 887–893.
Nishimoto I., Okamoto T., Matsuura Y., Takahashi S., Murayama Y., and Ogata E. (1993) Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o). Nature 362, 75–79.
Nishiyama K., Trapp B. D., Ikezu T., Ransohoff R. M., Tomita T., Iwatsubo T., et al. (1999) Caveolin-3 upregulation activates beta-secretase-mediated cleavage of the amyloid precursor protein in Alzheimer’s disease. J. Neurosci. 19, 6538–6548.
Nitsch R. M., Slack B. E., Wurtman R. J., and Growdon J. H. (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258, 304–307.
Nitsch R. M., Deng M., Growdon J. H., and Wurtman R. J. (1996) Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. J. Biol. Chem. 271, 4188–4194.
Nitsch R. M., Kim C., and Growdon J. H. (1998) Vasopressin and bradykinin regulate secretory processing of the amyloid protein precursor of Alzheimer’s disease. Neurochem. Res. 23, 807–814.
Nukina N. and Ihara Y. (1986) One of the antigenic determinants of paired helical filaments is related to tau protein. J. Biochem. (Tokyo) 99, 1541–1544.
Okamoto M. and Sudhof T. C. (1998) Mint 3: a ubiquitous mint isoform that does not bind to munc18-1 or -2. Eur. J. Cell Biol. 77, 161–165.
Okamoto T., Takeda S., Murayama Y., Ogata E., and Nishimoto I. (1995) Ligand-dependent G protein coupling function of amyloid transmembrane precursor. J. Biol. Chem. 270, 4205–4208.
Okamoto T., Takeda S., Giambarella U., Murayama Y., Matsui T., Katada T., 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, 3769–3677.
Palacino J. J., Berechid B. E., Alexander P., Eckman C., Younkin S., Nye J. S., and Wolozin B. (2000) Regulation of amyloid precursor protein processing by presenilin 1 (PS1) and PS2 in PS1 knockout cells. J. Biol. Chem. 275, 215–222.
Palmert M. R., Siedlak S. L., Podlisny M. B., Greenberg B., Shelton E. R., Chan H. W., et al. (1989) Soluble derivatives of the beta amyloid protein precursor of Alzheimer’s disease are labeled by antisera to the beta amyloid protein. Biochem. Biophys. Res. Commun. 165, 182–188.
Pan D. and Rubin G. M. (1997) Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 90, 271–280.
Pangalos M. N., Efthimiopoulos S., Shioi J., and Robakis N. K. (1995) The chondroitin sulfate attachment site of appican is formed by splicing out exon 15 of the amyloid precursor gene. J. Biol. Chem. 270, 10,388–10,391.
Parkin E. T., Turner A. J., and Hooper N. M. (1999) Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft protein. Biochem. J. 344, 23–30.
Perez R. G., Soriano S., Hayes J. D., Ostaszewski B., Xia W., Selkoe D. J., et al. (1999) Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42. J. Biol. Chem. 274, 18,851–18,856.
Petanceska S. S. and Gandy S. (1999) The phosphatidylinositol 3-kinase inhibitor wortmannin alters the metabolism of the Alzheimer’s amyloid precursor protein. J. Neurochem. 73, 2316–2320.
Petanceska S. S., Seeger M., Checler F., and Gandy S. (2000) Mutant presenilin 1 increases the levels of Alzheimer amyloid beta-peptide Abeta42 in late compartments of the constitutive secretory pathway. J. Neurochem. 74, 1878–1884.
Pinnix I., Council J. E., Roseberry B., Onstead L., Mallender W., Sucic J., and Sambamurti K. (2001a) Convertases other than furin cleave beta-secretase to its mature form. FASEB J. 15, 1810–1812.
Pinnix I., Musunuru U., Tun H., Sridharan A., Golde T., Eckman C., et al. (2001b) A novel gamma-secretase assay based on detection of the putative C-terminal fragment-gamma of amyloid beta protein precursor. J. Biol. Chem. 276, 481–487.
Podlisny M. B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J., 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.
Poirier J. (1994) Apolipoprotein E in animal models of CNS injury and in Alzheimer’s disease. Trends Neurosci. 17, 525–530.
Pollock N. J., Mirra S. S., Binder L. I., Hansen L. A., and Wood J. G. (1986) Filamentous aggregates in Pick’s disease, progressive supranuclear palsy, and Alzheimer’s disease share antigenic determinants with microtubule-associated protein, tau. Lancet 2, 1211.
Poorkaj P., Bird T. D., Wijsman E., Nemens E., Garruto R. M., Anderson L., et al. (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825.
Qi H., Rand M. D., Wu X., Sestan N., Wang W., Rakic P., et al. (1999) Processing of the notch ligand delta by the metalloprotease Kuzbanian. Science 283, 91–94.
Qiu W. Q., Walsh D. M., Ye Z., Vekrellis K., Zhang J., Podlisny M. B., et al. (1998) Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J. Biol. Chem. 273, 32,730–32,738.
Querfurth H. W., Wijsman E. M., St George-Hyslop P. H., and Selkoe D. J. (1995) Beta APP mRNA transcription is increased in cultured fibroblasts from the familial Alzheimer’s disease-1 family. Brain Res. Mol. Brain Res. 28, 319–337.
Refolo L. M., Eckman C., Prada C. M., Yager D., Sambamurti K., Mehta N., et al. (1999) Antisense-induced reduction of presenilin 1 expression selectively increases the production of amyloid beta 42 in transfected cells. J. Neurochem. 73, 2,383–2,388.
Refolo L. M., Pappolla M. A., Malester B., LaFrancois J., Bryant-Thomas T., Wang R., et al. (2000) Hyper-cholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol. Dis. 7, 321–331.
Refolo L. M., Pappolla M. A., LaFrancois J., Malester B., Schmidt S. D., Bryant-Thomas T., et al. (2001) A cholesterol-lowering drug reduces β-Amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol. Dis. 8, 822–832.
Riddell D. R., Christie G., Hussain I., and Dingwall C. (2001) Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr. Biol. 11, 1288–1293.
Robakis N. K., Ramakrishna N., Wolfe G., and Wisniewski H. M. (1987a) Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc. Natl. Acad. Sci. USA 84, 4190–4194.
Robakis N. K., Wisniewski H. M., Jenkins E. C., Devine-Gage E. A., Houck G. E., Yao X. L., et al. (1987b) Chromosome 21q21 sublocalisation of gene encoding beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques of people with Alzheimer disease and Down syndrome. Lancet 1, 384–385.
Roberds S. L., Anderson J., Basi G., Bienkowski M. J., Branstetter D. G., Chen K. S., et al. (2001) BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum. Mol. Genet. 10, 1317–1324.
Roberson M. R., Kolasa K., Parsons D. S., and Harrell L. E. (1997) Cholinergic denervation and sympathetic ingrowth result in persistent changes in hippocampal muscarinic receptors. Neuroscience 80, 413–418.
Roberts G. W., Gentleman S. M., Lynch A., and Graham D. I. (1991) Beta A4 amyloid protein deposition in brain after head trauma. Lancet 338, 1422–1423.
Rogaev E. I., Sherrington R., Rogaeva E. A., Levesque G., Ikeda M., Liang Y., 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.
Rogers J. T., Leiter L. M., McPhee J., Cahill C. M., Zhan S. S., Potter H., and Nilsson L. N. (1999) Translation of the Alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5′-untranslated region sequences. J. Biol. Chem. 274, 6421–6431.
Rohn T. T., Ivins K. J., Bahr B. A., Cotman C. W., and Cribbs D. H. (2000) A monoclonal antibody to amyloid precursor protein induces neuronal apoptosis. J. Neurochem. 74, 2331–2342.
Rosen D. R., Martin-Morris L., Luo L. Q., and 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., et al. (1989) Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s disease. N. Engl. J. Med. 320, 1446–1452.
Sabo S. L., Lanier L. M., Ikin A. F., Khorkova O., Sahasrabudhe S., Greengard P., and Buxbaum J. D. (1999) Regulation of beta-amyloid secretion by FE65, an amyloid protein precursor-binding protein. J. Biol. Chem. 274, 7952–7957.
Salbaum J. M., Weidemann A., Lemaire H. G., Masters C. L., and Beyreuther K. (1988) The promoter of Alzheimer’s disease amyloid A4 precursor gene. EMBO J. 7, 2807–2813.
Sambamurti K., Refolo L. M., Shioi J., Pappolla M. A., and Robakis N. K. (1992a) The Alzheimer’s amyloid precursor is cleaved intracellularly in the trans-Golgi network or in a post-Golgi compartment. Ann. NY Acad. Sci. 674, 118–128.
Sambamurti K., Shioi J., Anderson J. P., Pappolla M. A., and Robakis N. K. (1992b) Evidence for intracellular cleavage of the Alzheimer’s amyloid precursor in PC12 cells. J. Neurosci. Res. 33, 319–329.
Sambamurti K., Sevlever D., Koothan T., Refolo L. M., Pinnix I., Gandhi S., et al. (1999) Glycosylphosphatidylinositol-anchored proteins play an important role in the biogenesis of the Alzheimer’s amyloid beta-protein. J. Biol. Chem. 274, 26,810–26,814.
Sambamurti K., Pinnix I., Onstead L., Tun H., Younkin L., and Younkin S. G. (2000) Role of GPI-anchored proteins in β-secretase processing. Presented at World Alzheimer Congress, Washington, DC.
Sandbrink R., Masters C. L., and Beyreuther K. (1996) APP gene family. Alternative splicing generates functionally related isoforms. Ann. NY Acad. Sci. 777, 281–287.
Sastre M., Steiner H., Fuchs K., Capell A., Multhaup G., Condron M. M., et al. (2001) Presenilin-dependent {gamma}-secretase processing of {beta}-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep. 23, 23.
Saunders A. M., Trowers M. K., Shimkets R. A., Blakemore S., Crowther D. J., Mansfield T. A., et al. (2000) Therole of apolipoprotein E in Alzheimer’s disease: pharmacogenomic target selection. Biochim. Biophys. Acta 1502, 85–94.
Scheuner D., Eckman C., Jensen M., Song X., Citron M., Suzuki N., et al. (1996) Secreted amyloid beta-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. Nature Med. 2, 864–870.
Schubert D., LaCorbiere M., Saitoh T., and Cole G. (1989) Characterization of an amyloid beta precursor protein that binds heparin and contains tyrosine sulfate. Proc. Natl. Acad. Sci. USA 86, 2066–2069.
Scott J. N., Parhad I. M., and Clark A. W. (1991) Beta-amyloid precursor protein gene is differentially expressed in axotomized sensory and motor systems. Brain Res. Mol. Brain Res. 10, 315–325.
Selkoe D. J. (1991) The molecular pathology of Alzheimer’s disease. Neuron 6, 487–498.
Selkoe D. J. (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766.
Seubert P., Vigo-Pelfrey C., Esch F., Lee M., Dovey H., Davis D., et al. (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359, 325–327.
Seubert P., Oltersdorf T., Lee M. G., Barbour R., Blomquist C., Davis D. L., et al. (1993) Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature 361, 260–263.
Shaw K. T., Utsuki T., Rogers J., Yu Q. S., Sambamurti K., Brossi A., et al. (2001) Phenserine regulates translation of beta-amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development. Proc. Natl. Acad. Sci. USA 98, 7605–7610.
Shearman M. S., Beher D., Clarke E. E., Lewis H. D., Harrison T., Hunt P., et al. (2000) L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry 39, 8698–8704.
Sherrington R., Rogaev E. I., Liang Y., Rogaeva E. A., Levesque G., Ikeda M., et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760.
Shi X. P., Chen E., Yin K. C., Na S., Garsky V. M., Lai M. T., et al. (2001) The pro domain of beta-secretase does not confer strict zymogen-like properties but does assist proper folding of the protease domain. J. Biol. Chem. 276, 10,366–10,373.
Shioi J., Anderson J. P., Ripellino J. A., and Robakis N. K. (1992) Chondroitin sulfate proteoglycan form of the Alzheimer’s beta-amyloid precursor. J. Biol. Chem. 267, 13,819–13,822.
Shirra M. K. and Hansen U. (1998) LSF and NTF-1 share a conserved DNA recognition motif yet require different oligomerization states to form a stable protein-DNA complex. J. Biol. Chem. 273, 19,260–19,268.
Siman R., Card J. P., Nelson R. B., and Davis L. G. (1989) Expression of beta-amyloid precursor protein in reactive astrocytes following neuronal damage. Neuron 3, 275–285.
Simons M., Keller P., De Strooper B., Beyreuther K., Dotti C. G., Simons K. (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc. Natl. Acad. Sci. USA 95, 6460–6464.
Sinha S. and Lieberburg I. (1999) Cellular mechanisms of beta-amyloid production and secretion. Proc. Natl. Acad. Sci. USA 96, 11,049–11,053.
Sinha S., Anderson J. P., Barbour R., Basi G. S., Caccavello R., Davis D., et al. (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402, 537–540.
Sisodia S. S., Koo E. H., Beyreuther K., Unterbeck A., and Price D. L. (1990) Evidence that beta-amyloid protein in Alzheimer’s disease is not derived by normal processing. Science 248, 492–495.
Sisodia S. S. (1992) Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc. Natl. Acad. Sci. USA 89, 6075–6079.
Slack B. E., Nitsch R. M., Livneh E., Kunz G. M. Jr., Breu J., Eldar H., and Wurtman R. J. (1993) Regulation by phorbol esters of amyloid precursor protein release from Swiss 3T3 fibroblasts overexpressing protein kinase C alpha. J. Biol. Chem. 268, 21,097–21,101.
Slack B. E., Breu J., Livneh E., Eldar H., and Wurtman R. J. (1995) Phorbol ester stimulates choline uptake in Swiss 3T3 fibroblasts following introduction of the gene encoding protein kinase C alpha. Biochem. J. 305, 621–626.
Slack B. E., Breu J., Muchnicki L., and Wurtman R. J. (1997) Rapid stimulation of amyloid precursor protein release by epidermal growth factor: role of protein kinase C. Biochem. J. 327, 245–249.
Slack B. E., Ma L. K., and Seah C. C. (2001) Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-alpha converting enzyme. Biochem. J. 357, 787–794.
Smith R. P., Higuchi D. A., and Broze G. J. Jr. (1990) Platelet coagulation factor XIa-inhibitor, a form of Alzheimer amyloid precursor protein. Science 248, 1126–1128.
Song W. and Lahiri D. K. (1998a) Isolation of the genomic clone of the rhesus monkey beta-amyloid precursor protein. Biochem. Mol. Biol. Int. 46, 755–764.
Song W. and Lahiri D. K. (1998b) Molecular cloning of the promoter of the gene encoding the Rhesus monkey beta-amyloid precursor protein: structural characterization and a comparative study with other species. Gene 217, 151–164.
Song W. and Lahiri D. K. (1998c) Functional identification of the promoter of the gene encoding the Rhesus monkey beta-amyloid precursor protein. Gene 217, 165–176.
Spillantini M. G., Goedert M., Crowther R. A., Murrell J. R., Farlow M. R., and Ghetti B. (1997) Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc. Natl. Acad. Sci. USA 94, 4113–4118.
Spillantini M. G., Murrell J. R., Goedert M., Farlow M. R., Klug A., and Ghetti B. (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95, 7737–7741.
St George-Hyslop P. H., Tanzi R. E., Polinsky R. J., Haines J. L., Nee L., Watkins P. C., et al. (1987) The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235, 885–890.
Steiner H., Kostka M., Romig H., Basset G., Pesold B., Hardy J., et al. (2000) Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nature Cell Biol. 2, 848–851.
Sudo H., Jiang H., Yasukawa T., Hashimoto Y., Niikura T., Kawasumi M., et al. (2000) Antibody-regulated neurotoxic function of cell-surface beta-amyloid precursor protein. Mol. Cell Neurosci. 16, 708–723.
Sudol M., Sliwa K., and Russo T. (2001) Functions of WW domains in the nucleus. FEBS Lett. 490, 190–195.
Suo Z., Humphrey J., Kundtz A., Sethi F., Placzek A., Crawford F., and Mullan M. (1998) Soluble Alzheimers beta-amyloid constricts the cerebral vasculature in vivo. Neurosci. Lett. 257, 77–80.
Tanzi R. E., Gusella J. F., Watkins P. C., Bruns G. A., St George-Hyslop P., Van Keuren M. L., et al. (1987) Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235, 880–884.
Tanzi R. E., McClatchey A. I., Lamperti E. D., Villa-Komaroff L., Gusella J. F., and Neve R. L. (1988) Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer’s disease. Nature 331, 528–530.
Terry R. D. (1996) The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. J. Neuropathol. Exp. Neurol. 55, 1023–1025.
Terry R. D. (1998) The cytoskeleton in Alzheimer disease. J. Neural. Transm. Suppl. 53, 141–145.
Thinakaran G., Slunt H. H., and Sisodia S. S. (1995) Novel regulation of chondroitin sulfate glycosaminoglycan modification of amyloid precursor protein and its homologue, APLP2. J. Biol. Chem. 270, 16,522–16,525.
Thinakaran G., Borchelt D. R., Lee M. K., Slunt H. H., Spitzer L., Kim G., et al. (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181–190.
Thinakaran G., Harris C. L., Ratovitski T., Davenport F., Slunt H. H., Price D. L., (1997) Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J. Biol. Chem. 272, 28,415–28,422.
Thinakaran G., Regard J. B., Bouton C. M., Harris C. L., Price D. L., Borchelt D. R., and Sisodia S. S. (1998) Stable association of presenilin derivatives and absence of presenilin interactions with APP. Neurobiol. Dis. 4, 438–453.
Tomita T., Maruyama K., Saido T. C., Kume H., Shinozaki K., Tokuhiro S., et al. (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue. Proc. Natl. Acad. Sci. USA 94, 2025–2030.
Torroja L., Chu H., Kotovsky I., and White K. (1999a) Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport. Curr. Biol. 9, 489–492.
Torroja L., Packard M., Gorczyca M., White K., and Budnik V. (1999b) The Drosophila beta-amyloid precursor protein homolog promotes synapse differentiation at the neuromuscular junction. J. Neurosci. 19, 7793–7803.
Trommsdorff M., Borg J. P., Margolis B., and Herz J. (1998) Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein. J. Biol. Chem. 273, 33,556–33,560.
Tucker H. M., Kihiko M., Caldwell J. N., Wright S., Kawarabayashi T., Price D., et al. (2000) The plasmin system is induced by and degrades amyloid-beta aggregates. J. Neurosci. 20, 3937–3946.
Ulery P. G., Beers J., Mikhailenko I., Tanzi R. E., Rebeck G. W., Hyman B. T., and Strickland D. K. (2000) Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer’s disease. J. Biol. Chem. 275, 7410–7415.
Van Nostrand W. E., Schmaier A. H., Farrow J. S., and Cunningham D. D. (1990) Protease nexin-II (amyloid beta-protein precursor): a platelet alpha-granule protein. Science 248, 745–748.
Van Nostrand W. E. and Porter M. (1999) Plasmin cleavage of the amyloid beta-protein: alteration of secondary structure and stimulation of tissue plasminogen activator activity. Biochemistry 38, 11,570–11,576.
Vassar R., Bennett B. D., Babu-Khan S., Kahn S., Mendiaz E. A., Denis P., et al. (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741.
Vassilacopoulou D., Ripellino J. A., Tezapsidis N., Hook V. Y., and Robakis N. K. (1995) Full-length and truncated Alzheimer amyloid precursors in chromaffin granules: solubilization of membrane amyloid precursor is mediated by an enzymatic mechanism. J. Neurochem. 64, 2140–2146.
Vekrellis K., Ye Z., Qiu W. Q., Walsh D., Hartley D., Chesneau V., et al. (2000) Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J. Neurosci. 20, 1657–1665.
Vidal R., Frangione B., Rostagno A., Mead S., Revesz T., Plant G., and Ghiso J. (1999) A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399, 776–781.
von Koch C. S., Zheng H., Chen H., Trumbauer M., Thinakaran G., van der Ploeg L. H., et al. (1997) Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol. Aging 18, 661–669.
Walter J., Capell A., Hung A. Y., Langen H., Schnolzer M., Thinakaran G., et al. (1997) Ectodomain phosphorylation of beta-amyloid precursor protein at two distinct cellular locations. J. Biol. Chem. 272, 1896–1903.
Walter J., Schindzielorz A., Hartung B., and Haass C. (2000) Phosphorylation of the beta-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2. J. Biol. Chem. 275, 23,523–23,529.
Wang R., Meschia J. F., Cotter R. J., and Sisodia S. S. (1991) Secretion of the beta/A4 amyloid precursor protein. Identification of a cleavage site in cultured mammalian cells. J. Biol. Chem. 266, 16,960–16,964.
Wang R., Sweeney D., Gandy S. E., and Sisodia S. S. (1996) The profile of soluble amyloid beta protein in cultured cell media: Detection and quantification of amyloid beta protein and variants by immunoprecipitaion-mass spectrometry J. Biol. Chem. 271, 31,894–31,902.
Wasco W., Bupp K., Magendantz M., Gusella J. F., Tanzi R. E., and 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, 10,758–10,762.
Wasco W., Gurubhagavatula S., Paradis M. D., Romano D. M., Sisodia S. S., Hyman B. T., et al. (1993) Isolation and characterization of APLP2 encoding a homologue of the Alzheimer’s associated amyloid beta protein precursor. Nature Genet. 5, 95–100.
Weidemann A., Konig G., Bunke D., Fischer P., Salbaum J. M., Masters C. L., and Beyreuther K. (1989) Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell 57, 115–126.
Wickelgren I. (1997) Estrogen stakes claim to cognition. Science 276, 675–678.
Wiltfang J., Esselmann H., Cupers P., Neumann M., Kretzschmar H., Beyermann M., et al. (2001) Elevation of Abeta peptide 2-42 in sporadic and familial Alzheimer’s disease and its generation in PS1 knockout cells. J. Biol. Chem. in press.
Wisniewski H. M. and Wrzolek M. (1988) Pathogenesis of amyloid formation in Alzheimer’s disease, Down’s syndrome and scrapie. Ciba Found. Symp. 135, 224–238.
Wolfe M. S., Citron M., Diehl T. S., Xia W., Donkor I. O., and Selkoe D. J. (1998) A substrate-based difluoro ketone selectively inhibits Alzheimer’s gamma-secretase activity. J. Med. Chem. 41, 6–9.
Wolfe M. S., Xia W., Ostaszewski B. L., Diehl T. S., Kimberly W. T., and Selkoe D. J. (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398, 513–517.
Wolfe M. S. (2001) Presenilin and gamma-secretase: structure meets function. J. Neurochem. 76, 1615–1620.
Wolozin B., Kellman W., Ruosseau P., Celesia G. G., and Siegel G. (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57, 1439–1443.
Wolozin B. (2001) A fluid connection: cholesterol and Abeta. Proc. Natl. Acad. Sci. USA 98, 5371–5373.
Wolozin B. L., Basaric-Keys J., Canter R., Li Y., Vanderputten D., and Sunderland T. (1996) Differential regulation of APP secretion by apolipoprotein E3 and E4. Ann. NY Acad. Sci. 777, 322–326.
Wong C. W., Quaranta V., and Glenner G. G. (1985) Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related. Proc. Natl. Acad. Sci. USA 82, 8729–8732.
Wood J. G., Mirra S. S., Pollock N. J., and Binder L. I. (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.
Wu A., Pangalos M. N., Efthimiopoulos S., Shioi J., and Robakis N. K. (1997) Appican expression induces morphological changes in C6 glioma cells and promotes adhesion of neural cells to the extracellular matrix. J. Neurosci. 17, 4987–4993.
Xia W., Ray W. J., Ostaszewski B. L., Rahmati T., Kimberly W. T., Wolfe M. S., et al. (2000) Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta-protein generation. Proc. Natl. Acad. Sci. USA 97, 9299–9304.
Xu H., Gouras G. K., Greenfield J. P., Vincent B., Naslund J., Mazzarelli L., et al. (1998) Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nature Med. 4, 447–451.
Yamatsuji T., Matsui T., Okamoto T., Komatsuzaki K., Takeda S., Fukumoto H., et al. (1996) G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer’s disease-associated mutants of APP. Science 272, 1349–1352.
Yamazaki T., Koo E. H., and Selkoe D. J. (1997) Cell surface amyloid beta-protein precursor colocalizes with beta 1 integrins at substrate contact sites in neural cells. J. Neurosci. 17, 1004–1010.
Yamazaki T., Chang T. Y., Haass C., and Ihara Y. (2001) Accumulation and aggregation of Amyloid β-protein in late endosomes of Niemann-Pick Type C cells. J. Biol. Chem. 276, 4454–4460.
Yamin R., Malgeri E. G., Sloane J. A., McGraw W. T., and Abraham C. R. (1999) Metalloendopeptidase EC 3.4.24.15 is necessary for Alzheimer’s amyloidbeta peptide degradation. J. Biol. Chem. 274, 18,777–18,784.
Yan R., Bienkowski M. J., Shuck M. E., Miao H., Tory M. C., Pauley A. M., et al. (1999) Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 402, 533–537.
Yanagisawa K. and Ihara Y. (1998) GM1 ganglioside-bound amyloid beta-protein in Alzheimer’s disease brain. Neurobiol. Aging 19, S65-S67.
Yankner B. A., Duffy L. K., and Kirschner D. A. (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250, 279–282.
Yasojima K., Akiyama H., McGeer E. G., and McGeer P. L. (2001) Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide. Neurosci. Lett. 297, 97–100.
Younkin S. G. (1998) The role of A beta 42 in Alzheimer’s disease. J. Physiol. Paris 92, 289–292.
Yu G., Nishimura M., Arawaka S., Levitan D., Zhang L., Tandon A., et al. (2000). Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and beta APP processing. Nature 407, 48–54.
Yu C., Kim S. H., Ikeuchi T., Xu H., Gasparini L., Wang R., and Sisodia S. S. (2001) Characterization of a presenilin-mediated APP carboxyl terminal fragment gamma CTFgamma: evidence for distinct mechanisms involved in gamma-secretase processing of the APP and notch 1 transmembrane domains. J. Biol. Chem., in press.
Zambrano N., Buxbaum J. D., Minopoli G., Fiore F., De Candia P., De Renzis S., et al. (1997) Interaction of the phosphotyrosine interaction/phosphotyrosine binding-related domains of Fe65 with wild-type and mutant Alzheimer’s beta-amyloid precursor proteins. J. Biol. Chem. 272, 6399–6405.
Zambrano N., Minopoli G., de Candia P., and Russo T. (1998) The Fe65 adaptor protein interacts through its PID1 domain with the transcription factor CP2/LSF/LBP1. J. Biol. Chem. 273, 20,128–20,133.
Zhang W., Espinoza D., Hines V., Innis M., Mehta P., and Miller D. L. (1997) Characterization of beta-amyloid peptide precursor processing by the yeast Yap3 and Mkc7 proteases. Biochim. Biophys. Acta 1359, 110–122.
Zhang Z., Nadeau P., Song W., Donoviel D., Yuan M., Bernstein A., and Yankner B. A. (2000) Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nature Cell Biol. 2, 463–465.
Zheng P., Eastman J., Vande Pol S., and Pimplikar S. W. (1998) PAT1, a microtubule-interacting protein, recognizes the basolateral sorting signal of amyloid precursor protein. Proc. Natl. Acad. Sci. USA 95, 14,745–14,750.
Zhong Z., Higaki J., Murakami K., Wang Y., Catalano R., Quon D., and Cordell B. (1994) Secretion of beta-amyloid precursor protein involves multiple cleavage sites. J. Biol. Chem. 269, 627–632.
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Sambamurti, K., Greig, N.H. & Lahiri, D.K. Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer’s disease. Neuromol Med 1, 1–31 (2002). https://doi.org/10.1385/NMM:1:1:1
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DOI: https://doi.org/10.1385/NMM:1:1:1