β-Secretase inhibition for the treatment of Alzheimer's disease -: promise and challenge

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 (Abeta42), 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 Abeta42 by specific inhibition of the key proteases required for Abeta42 generation is a major focus of research into AD therapy. The identification of beta-secretase, the aspartic protease that generates the N-terminus of Abeta42, 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.