Piperidine Acetic Acid Based γ-Secretase Modulators Directly Bind to Presenilin-1

A beta 42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. gamma-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of A beta 42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the gamma-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the gamma-secretase complex leading to the observed modulation of gamma-secretase activity.