β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the β-secretase enzyme
required for the production of the neurotoxic β-amyloid (Aβ) peptide that is widely
considered to have a crucial early role in the etiology of Alzheimer?s disease (AD). As a
result, BACE1 has emerged as a prime drug target for reducing the levels of Aβ in the AD
brain, and the development of BACE1 inhibitors as therapeutic agents is being vigorously
pursued. It has proven difficult for the pharmaceutical industry to design BACE1 inhibitor
drugs that pass the blood?brain barrier, however this challenge has recently been met and
BACE1 inhibitors are now in human clinical trials to test for safety and efficacy in AD
patients and individuals with pre-symptomatic AD. Initial results suggest that some of these
BACE1 inhibitor drugs are well tolerated, although others have dropped out because of
toxicity and 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 mice that lack BACE1, concerns have emerged about potential mechanism-based side
effects of BACE1 inhibitor drugs with chronic administration. It is hoped that a therapeutic
window can be achieved that balances safety and efficacy. This review summarizes the
current state of progress in the development of BACE1 inhibitor drugs and the evaluation of
their therapeutic potential for AD.
AlzheimeResearch.com | Finding a cure for Alzheimer's disease
