β-Secretase Inhibition

The β-secretase enzyme, also known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), is required for production of the β-amyloid (Aβ) peptide that has a crucial early role in Alzheimer's disease (AD) pathogenesis. β-Secretase/BACE1 is a prime therapeutic target for reducing cerebral Aβ levels, and the development of BACE1 inhibitor drugs is being vigorously pursued. Indeed, brain-permeable BACE1 inhibitors have recently entered clinical trials to test for safety and efficacy in AD patients and individuals with presymptomatic AD. Initial results suggest that some of these BACE1 inhibitor drugs are well tolerated, although it is still too early to know whether any will be effective for the prevention or treatment of AD. Additionally, based on newly identified BACE1 substrates and phenotypes of BACE1-deficient mice, concerns have emerged about potential mechanism-based side effects of BACE1 inhibitor drugs. It is hoped that a therapeutic window can be achieved that balances safety and efficacy.