Closing in on the amyloid cascade recent insights into the cell biology of Alzheimer's disease

Accumulation of the amyloid-beta (AP) peptide in the central nervous system (CNS) is considered by many to be the crucial pathological insult that ultimately leads to the development of Alzheimer's disease (AD). Regulating the production and/or aggregation of A beta could therefore be of considerable benefit to patients afflicted with AD. It has long been known that A beta is derived from the proteolytic processing of the amyloid precursor protein (APP) by two enzymatic activities, beta -secretase and gamma -secretase. Recent breakthroughs have led to the identification of the aspartyl protease BACE (beta -site APP-cleaving enzyme) as beta -secretase and the probable identification of the presenilin proteins as gamma -secretases. This review discusses what is know about BACE and the presenilins, focusing on their capacity as secretases, as well as the options for therapeutic advancement the careful characterization of these proteins will provide. These findings are presented in the context of the "amyloid cascade hypothesis" and its physiological relevance in AD pathogenesis.