Target of γ-secretase modulators, presenilin marks the spot

Abstract

γ-Secretase modulators, or GSMs, which reduce the production of Aβ42, have emerged as a promising class of compounds for the treatment of Alzheimer's disease (AD). The target and mechanism of action of GSMs have been controversial as of late, with some evidence suggesting that GSMs function by binding the substrate, amyloid precursor protein (APP), and others claiming action through direct modulation of the enzyme, γ-secretase. In this issue of The EMBO Journal, Ohki et al (2011) show that piperidine acetic acid-based GSMs directly bind to presenilin, the catalytic subunit of γ-secretase; and GSM binding induces conformational changes in γ-secretase, leading to a shift in the cleavage site specificity of APP from longer to shorter peptide fragments. © 2011 European Molecular Biology Organization | All Rights Reserved.