Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease
Genevieve Evin,1,2 Adel Barakat2
1Oxidation Biology Laboratory, Mental Health Research Institute, Florey Institute of Neuroscience and Mental Health, University of Melbourne, 2Department of Pathology, University of Melbourne, Parkville, VIC, Australia
Abstract: Alzheimer's disease (AD) is the major cause of dementia in the elderly and an unmet clinical challenge. A variety of therapies that are currently under development are directed to the amyloid cascade. Indeed, the accumulation and toxicity of amyloid-β (Aβ) is believed to play a central role in the etiology of the disease, and thus rational interventions are aimed at reducing the levels of Aβ in the brain. Targeting β-site amyloid precursor protein-cleaving enzyme (BACE)-1 represents an attractive strategy, as this enzyme catalyzes the initial and rate-limiting step in Aβ production. Observation of increased levels of BACE1 and enzymatic activity in the brain, cerebrospinal fluid, and platelets of patients with AD and mild cognitive impairment supports the potential benefits of BACE1 inhibition. Numerous potent inhibitors have been generated, and many of these have been proved to lower Aβ levels in the brain of animal models. Over 10 years of intensive research on BACE1 inhibitors has now culminated in advancing half a dozen of these drugs into human trials, yet translating the in vitro and cellular efficacy of BACE1 inhibitors into preclinical and clinical trials represents a challenge. This review addresses the promises and also the potential problems associated with BACE1 inhibitors for AD therapy, as the complex biological function of BACE1 in the brain is becoming unraveled.
Keywords: amyloid, dementia, secretase, aspartyl protease, neuregulin
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