2. Academic Validation
  3. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain

Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain

  • J Neurochem. 2001 Jan;76(1):173-81. doi: 10.1046/j.1471-4159.2001.00012.x.
H F Dovey 1,  V John,  J P Anderson,  L Z Chen,  P de Saint Andrieu,  L Y Fang,  S B Freedman,  B Folmer,  E Goldbach,  E J Holsztynska,  K L Hu,  K L Johnson-Wood,  S L Kennedy,  D Kholodenko,  J E Knops,  L H Latimer,  M Lee,  Z Liao,  I M Lieberburg,  R N Motter,  L C Mutter,  J Nietz,  K P Quinn,  K L Sacchi,  P A Seubert,  G M Shopp,  E D Thorsett,  J S Tung,  J Wu,  S Yang,  C T Yin,  D B Schenk,  P C May,  L D Altstiel,  M H Bender,  L N Boggs,  T C Britton,  J C Clemens,  D L Czilli,  D K Dieckman-McGinty,  J J Droste,  K S Fuson,  B D Gitter,  P A Hyslop,  E M Johnstone,  W Y Li,  S P Little,  T E Mabry,  F D Miller,  J E Audia
Affiliations

Affiliation

  • 1 Elan Pharmaceuticals, Inc., South San Francisco, CA 94080, USA.
PMID: 11145990 DOI: 10.1046/j.1471-4159.2001.00012.x
Abstract

Converging lines of evidence implicate the beta-amyloid peptide (Ass) 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 Ass 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 Ass peptide drives the neuropathology observed in Alzheimer's disease.

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