Protease inhibitors as potential disease-modifying therapeutics for Alzheimer's disease.

The current lack of an effective treatment for Alzheimer's disease (AD) has fuelled an intense search for novel therapies for this neurodegenerative condition. Aberrant production or decreased clearance of amyloid-beta peptides is widely accepted to be causative for AD. Amyloid-beta peptides are produced by sequential processing of the beta-amyloid precursor protein by the two aspartyl-type proteases beta-secretase and gamma-secretase. Because proteases are generally classified as druggable, these secretases are a centre of attraction for various drug discovery efforts. Although a large number of specific drug-like gamma-secretase inhibitors have been discovered, progress towards the clinic has been slowed by the broad substrate specificity of this unusual intramembrane-cleaving enzyme. In particular, the Notch receptor depends on gamma-secretase for its signalling function and, thus, gamma-secretase inhibition produces distinct phenotypes related to a disturbance of this pathway in preclinical animal models. The main task now is to define the therapeutic window in man between desired central efficacy and Notch-related side effects. In contrast, most studies with knockout animals have indicated that beta-secretase inhibition may have minimal adverse effects; however, the properties of the active site of this enzyme make it difficult to find small-molecule inhibitors that bind with high affinity. In most instances, inhibitors are large and peptidic in nature and, therefore, unsuitable as drug candidates. Thus, there are many issues associated with the development of protease inhibitors for AD that must be addressed before they can be used to test the 'amyloid cascade hypothesis' in the clinic. The outcomes of such trials will provide new directions to the scientific community and hopefully new treatment options for AD patients.