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Titolo:
BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics
Autore:
Roberds, SL; Anderson, J; Basi, G; Bienkowski, MJ; Branstetter, DG; Chen, KS; Freedman, SB; Frigon, NL; Games, D; Hu, K; Johnson-Wood, K; Kappenman, KE; Kawabe, TT; Kola, I; Kuehn, R; Lee, M; Liu, WQ; Motter, R; Nichols, NF; Power, M; Robertson, DW; Schenk, D; Schoor, M; Shopp, GM; Shuck, ME; Sinha, S; Svensson, KA; Tatsuno, G; Tintrup, H; Wijsman, J; Wright, S; McConlogue, L;
Indirizzi:
Pharmacia Corp, Dept Genom, Kalamazoo, MI 49007 USA Pharmacia Corp Kalamazoo MI USA 49007 Dept Genom, Kalamazoo, MI 49007 USA Pharmacia Corp, Dept Cell & Mol Biol, Kalamazoo, MI 49007 USA Pharmacia Corp Kalamazoo MI USA 49007 & Mol Biol, Kalamazoo, MI 49007 USA Pharmacia Corp, Dept Invest Toxicol, Kalamazoo, MI 49007 USA Pharmacia Corp Kalamazoo MI USA 49007 st Toxicol, Kalamazoo, MI 49007 USA Pharmacia Corp, Dept Pharmacol, Kalamazoo, MI 49007 USA Pharmacia Corp Kalamazoo MI USA 49007 Pharmacol, Kalamazoo, MI 49007 USA Pharmacia Corp, Dept Neurosci, Kalamazoo, MI 49007 USA Pharmacia Corp Kalamazoo MI USA 49007 t Neurosci, Kalamazoo, MI 49007 USA Elan Pharmaceut, S San Francisco, CA 94080 USA Elan Pharmaceut S San Francisco CA USA 94080 San Francisco, CA 94080 USA Artemis Pharmaceut GmbH, D-51063 Koeln, Germany Artemis Pharmaceut GmbH Koeln Germany D-51063 bH, D-51063 Koeln, Germany
Titolo Testata:
HUMAN MOLECULAR GENETICS
fascicolo: 12, volume: 10, anno: 2001,
pagine: 1317 - 1324
SICI:
0964-6906(20010601)10:12<1317:BKMAHD>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMYLOID PRECURSOR PROTEIN; IN-VIVO; PRESENILIN-1; CLEAVAGE; PEPTIDE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Roberds, SL Pharmacia Corp, Dept Genom, 301 Henrietta St, Kalamazoo, MI 49007 USA Pharmacia Corp 301 Henrietta St Kalamazoo MI USA 49007 007 USA
Citazione:
S.L. Roberds et al., "BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics", HUM MOL GEN, 10(12), 2001, pp. 1317-1324

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major components of plaque, beta -amyloid peptides (APs), are produced from amyloid precursor protein (APP) by the activity of beta- and gamma -secretases. beta -secretase activity cleaves APP to define the N-terminus of the A beta1-x peptides and, therefore, has been a long-sought therapeutic target for treatment of AD. The gene encoding a beta -secretase for beta-siteAPP cleaving enzyme (BACE) was identified recently. However, it was not known whether BACE was the primary beta -secretase in mammalian brain nor whether inhibition of beta -secretase might have effects in mammals that wouldpreclude its utility as a therapeutic target. In the work described herein, we generated two lines of BACE knockout mice and characterized them for pathology, beta -secretase activity and A beta production. These mice appeared to develop normally and showed no consistent phenotypic differences fromtheir wild-type littermates, including overall normal tissue morphology and brain histochemistry, normal blood and urine chemistries, normal blood-cell composition, and no overt behavioral and neuromuscular effects. Brain and primary cortical cultures from BACE knockout mice showed no detectable beta -secretase activity, and primary cortical cultures from BACE knockout mice produced much less A beta from APP. The findings that BACE is the primary beta -secretase activity in brain and that loss of beta -secretase activity produces no profound phenotypic defects with a concomitant reduction in beta -amyloid peptide clearly indicate that BACE is an excellent therapeutic target for treatment of AD.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/01/20 alle ore 21:37:49