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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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

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.[1]


  1. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. Dovey, H.F., John, V., Anderson, J.P., Chen, L.Z., de Saint Andrieu, P., Fang, L.Y., Freedman, S.B., Folmer, B., Goldbach, E., Holsztynska, E.J., Hu, K.L., Johnson-Wood, K.L., Kennedy, S.L., Kholodenko, D., Knops, J.E., Latimer, L.H., Lee, M., Liao, Z., Lieberburg, I.M., Motter, R.N., Mutter, L.C., Nietz, J., Quinn, K.P., Sacchi, K.L., Seubert, P.A., Shopp, G.M., Thorsett, E.D., Tung, J.S., Wu, J., Yang, S., Yin, C.T., Schenk, D.B., May, P.C., Altstiel, L.D., Bender, M.H., Boggs, L.N., Britton, T.C., Clemens, J.C., Czilli, D.L., Dieckman-McGinty, D.K., Droste, J.J., Fuson, K.S., Gitter, B.D., Hyslop, P.A., Johnstone, E.M., Li, W.Y., Little, S.P., Mabry, T.E., Miller, F.D., Audia, J.E. J. Neurochem. (2001) [Pubmed]
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