Beta-secretase inhibition for the treatment of Alzheimer's disease--promise and challenge

Abstract

As the number of cases of Alzheimer's disease (AD) rises in all developed countries, the unmet medical need for disease-modifying pharmacotherapy continues to grow. Much of AD research has been focused on the amyloid cascade hypothesis, which states that amyloid-beta-42 (A beta 42), a proteolytic derivative of the large transmembrane protein amyloid precursor protein (APP), plays an early and crucial role in all cases of AD. Consequently, blocking the production of A beta 42 by specific inhibition of the key proteases required for A beta 42 generation is a major focus of research into AD therapy. The identification of beta-secretase, the aspartic protease that generates the N-terminus of A beta 42, has triggered a race to develop drug-like inhibitors of this enzyme, which has become one of the major AD targets. Although the biology of beta-secretase holds great promise, it will be challenging to generate drug-like inhibitors of this unusual enzyme.