Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease of the central nervous system that causes dementia in a large percentage of the aged population and for which there are only symptomatic treatments. Disease-modifying therapies that are currently being pursued are based on the amyloid cascade theory. This states that accumulation of amyloid β (Aβ) in the brain triggers a cascade of cellular events leading to neurodegeneration. Aβ, which is the major constituent of amyloid plaques, is a peptidic fragment derived from proteolytic processing of the amyloid precursor protein (APP) by sequential cleavages that involve β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase. Targeting BACE1 is a rational approach as its cleavage of APP is the rate-limiting step in Aβ production and this enzyme is elevated in the brain of patients with AD. Furthermore, knocking out the BACE1 gene in mice showed little apparent consequences. Ten years of intensive research has led to the design of efficacious BACE1 inhibitors with favorable pharmacological properties. Several drug candidates have shown promising results in animal models, as they reduce amyloid plaque pathology in the brain and rescue cognitive deficits. Phase I clinical trials indicate that these drugs are well tolerated, and the results from further trials in AD patients are now awaited eagerly. Yet, recent novel information on BACE1 biology, and the discovery that BACE1 cleaves a selection of substrates involved in myelination, retinal homeostasis, brain circuitry, and synaptic function, alert us to potential side effects of BACE1 inhibitors that will require further evaluation to provide a safe therapy for AD.
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The authors acknowledge funding support from the Judith Jane Mason and Harold Stannett Williams Memorial Foundation. The authors have no conflicts of interest that are directly relevant to the content of this review.
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Evin, G., Hince, C. BACE1 as a Therapeutic Target in Alzheimer’s Disease: Rationale and Current Status. Drugs Aging 30, 755–764 (2013). https://doi.org/10.1007/s40266-013-0099-3
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DOI: https://doi.org/10.1007/s40266-013-0099-3