BACE1: Expression, regulation, and therapeutic potential of the major Alzheimer's disease beta-Secretase

The number of individuals afflicted by Alzheimer's disease (AD) worldwide is rapidly rising and we, as a society, are approaching a critical junction in the development of new therapeutics aimed at slowing or preventing the onset of this devastating neurodegenerative disease. The prevailing theory in the field pinpoints the amyloid β peptide (Aβ) as the causal agent of the disease and thus strategies that target the production, deposition, and clearance of Aβ in the brain continue to be at the forefront of therapeutic interventions. Aβ is produced through a series of proteolytic cleavage events, with β-secretase (BACE1) being the rate-limiting enzymatic activity needed to begin the liberation of the Aβ peptide from the larger amyloid precursor protein (APP). As such, BACE1 itself has become a prime therapeutic target for AD. Still, over ten years after its discovery, only a handful of compounds targeting BACE1 have reached clinical trial, indicating that complex challenges continue to persist. This short review will focus on the cellular and molecular characteristics of BACE1, its role in APP processing and in AD, and its potential as a therapeutic target for AD.