Secretases as therapeutic targets for Alzheimer's disease.

ABSTRACT

Accumulation of amyloid-ß (Aß) is widely accepted as the key instigator of Alzheimer's disease (AD). The proposed mechanism is that accumulation of Aß results in inflammatory responses, oxidative damages, neurofibrillary tangles and, subsequently, neuronal/synaptic dysfunction and neuronal loss. Given the critical role of Aß in the disease process, the proteases that produce this peptide are obvious targets. The goal would be to develop drugs that can inhibit the activity of these targets. Protease inhibitors have proved very effective for treating other disorders such as AIDS and hypertension. Mutations in APP (amyloid-ß precursor protein), which flanks the Aß sequence, cause early-onset familial AD, and evidence has pointed to the APP-to-Aß conversion as a possible therapeutic target. Therapies aimed at modifying Aß-related processes aim higher up the cascade and are therefore more likely to be able to alter the progression of the disease. However, it is not yet fully known whether the increases in Aß levels are merely a result of earlier events that were already causing the disease.