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. Amyloid β peptides are the predominant species found in the amyloid plaques associated with AD. Upon γ‐secretase cleavage within the transmembrane region of the APP, Aβ peptides of varying length are released. Several studies have shown that the longer and more hydrophopic Aβ peptides, such as Aβ42, are more prone to aggregate and are likely the major toxic species. Moreover, it appears that it is the ratio of Aβ42 to Aβ40, rather than total Aβ levels, which is the key determinant for disease progression (Karran et al , 2011). Consequently, γ‐secretase has become an appealing drug target for the reduction of Aβ production. However, γ‐secretase is thought to process a plethora of substrates in addition to APP—most notably, Notch receptor proteins. Therefore, the importance of selective γ‐secretase inhibition has become increasingly obvious in recent years, and was demonstrated by the failure during phase III clinical trials of Eli‐Lilly's Semagacestat, a non‐selective γ‐secretase inhibitor (GSI). Semagacestat treatment resulted in slightly worse cognition scores and an increase …