Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions

Abstract

Alzheimer's disease (AD) is characterized by the extracellular deposition of the beta-amyloid protein (Abeta). Abeta is a fragment of a much larger precursor protein, the amyloid precursor protein (APP). Sequential proteolytic cleavage of APP by beta-secretase and gamma-secretase liberates Abeta from APP. The aspartyl protease BACE1 (beta-site APP-cleaving enzyme 1) catalyses the rate-limiting step in the production of Abeta, and as such it is considered to be a major target for drug development in Alzheimer's disease. However, the development of a BACE1 inhibitor therapy is problematic for two reasons. First, BACE1 has been found to have important physiological roles. Therefore, inhibition of the enzyme could have toxic consequences. Second, the active site of BACE1 is relatively large, and many of the bulky compounds that are needed to inhibit BACE1 activity are unlikely to cross the blood-brain barrier. This review focuses on the structure BACE1, current therapeutic strategies based on developing active-site inhibitors, and new approaches to therapy involving targeting the expression or post-translational regulation of BACE1.