Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1

作者：Ohki Yu; Higo Takuya; Uemura Kengo; Shimada Naoaki; Osawa Satoko; Berezovska Oksana; Yokoshima Satoshi; Fukuyama Tohru; Tomita Taisuke^*; Iwatsubo Takeshi

来源：The EMBO Journal, 2011, 30(23): 4815-4824.

DOI：10.1038/emboj.2011.372

• Alzheimer
• modulation
• protease
• secretase

Amyloid-beta peptide ending at the 42nd residue (A beta 42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on A beta 42 production are termed gamma-secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that a phenylpiperidine-type compound GSM-1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1) by photoaffinity labelling experiments combined with limited digestion. Binding of GSM-1 affected the structure of the initial substrate binding and the catalytic sites of the gamma-secretase, thereby decreasing production of A beta 42, possibly by enhancing its conversion to A beta 38. These data indicate an allosteric action of GSM-1 by directly binding to the TMD1 of PS1, pinpointing the target structure of the phenylpiperidine-type GSMs. The EMBO Journal (2011) 30, 4815-4824. doi:10.1038/emboj.2011.372; Published online 14 October 2011

• 出版日期2011-11-30