BACE1 in Alzheimer's disease

Targeting BACE1 (beta-site APP cleaving enzyme 1 or beta-secretase) is the focus of Alzheimer's disease (AD) research because this aspartyl protease is involved in the abnormal production of beta amyloid plaques (A beta), the hallmark of its pathophysiology. Evidence suggests that there is a strong connection between AD and BACE1. As such, strategies to inhibit A beta formation in the brain should prove beneficial for AD treatment. A beta, the product of the large type1 trans-membrane protein amyloid precursor protein (APP), is produced in a two-step proteolytic process initiated by BACE1 (beta-secretase) and followed by gamma-secretase. Due to its apparent rate limiting function, BACE1 appears to be a prime target to prevent A beta generation in AD. Following its discovery, the BACE1 has been cloned, its structure solved, novel physiologic substrates discovered and numerous inhibitors developed. This review focuses on elucidating the role of BACE1 to facilitate drug development in the treatment of AD. (C) 2012 Elsevier B.V. All rights reserved.