Secretases as therapeutic targets for Alzheimer's disease

Accumulation of amyloid-beta (A beta) is widely accepted as the key instigator of Alzheimer's disease (AD). The proposed mechanism is that accumulation of A beta results in inflammatory responses, oxidative damages, neurofibrillary tangles and, subsequently, neuronal/synaptic dysfunction and neuronal loss. Given the critical role of A beta 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-beta precursor protein), which flanks the A beta sequence, cause early-onset familial AD, and evidence has pointed to the APP-to-A beta conversion as a possible therapeutic target. Therapies aimed at modifying A beta-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 A beta levels are merely a result of earlier events that were already causing the disease. (C) 2010 Elsevier Inc. All rights reserved.