Abstract
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.
Original language | English (US) |
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Journal | Alzheimer's Research and Therapy |
Volume | 6 |
Issue number | 9 |
DOIs | |
State | Published - Dec 24 2014 |
Funding
R.V. has consulted for Eisai, Lilly, and Vitae Pharmaceutical Co.; his research funding sources include NIH R01AG022560, R01AG030142, Cure Alzheimer’s Fund, Baila Foundation, BrightFocus Foundation, and the Alzheimer’s Association.
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
- Cognitive Neuroscience