期刊
JOURNAL OF NEUROCHEMISTRY
卷 76, 期 1, 页码 173-181出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1046/j.1471-4159.2001.00012.x
关键词
amyloid beta-peptide; Alzheimer's disease therapeutics; gamma-secretase; protease inhibitors
Converging lines of evidence implicate the beta-amyloid peptide (A beta) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma -secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of A beta in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma -secretase inhibitors will enable a clinical examination of the A beta hypothesis that A beta peptide drives the neuropathology observed in Alzheimer's disease.
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