gamma-secretase: Never more enigmatic

It is widely believed that the pathogenesis of Alzheimer's disease (AD) is intimately, if not causatively, associated with the deposition of similar t o4 kDa beta -amyloid (A beta) peptides in the cerebral cortex and hippocamp us of affected individuals. A beta peptides are liberated from transmembran e proteins, termed beta -amyloid precursor proteins (APP), by the concerted action of beta- and gamma -secretase(s). Whereas the identity of beta -sec retase is no longer in question, the identity of gamma -secretase, which is responsible for the intramembranous processing of APP, has never been more enigmatic. Considerable evidence has accrued to impugn the presenilins (PS ) as the executioners of intramembranous processing of APR Here, we summari ze these observations and review recent evidence that argues against the pr evailing hypothesis that PS function as gamma -secretases.