Elsevier

The Lancet Neurology

Volume 13, Issue 3, March 2014, Pages 319-329
The Lancet Neurology

Review
Targeting the β secretase BACE1 for Alzheimer's disease therapy

https://doi.org/10.1016/S1474-4422(13)70276-XGet rights and content

Summary

The β secretase, widely known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), initiates the production of the toxic amyloid β (Aβ) that plays a crucial early part in Alzheimer's disease pathogenesis. BACE1 is a prime therapeutic target for lowering cerebral Aβ concentrations in Alzheimer's disease, and clinical development of BACE1 inhibitors is being intensely pursued. Although BACE1 inhibitor drug development has proven challenging, several promising BACE1 inhibitors have recently entered human clinical trials. The safety and efficacy of these drugs are being tested at present in healthy individuals and patients with Alzheimer's disease, and will soon be tested in individuals with presymptomatic Alzheimer's disease. Although hopes are high that BACE1 inhibitors might be efficacious for the prevention or treatment of Alzheimer's disease, concerns have been raised about potential mechanism-based side-effects of these drugs. The potential of therapeutic BACE1 inhibition might prove to be a watershed in the treatment of Alzheimer's disease.

Introduction

Alzheimer's disease is characterised by the cerebral accumulation of extracellular deposits called amyloid plaques that are composed of amyloid β peptides (Aβ) of 38–43 aminoacids. Amyloid β plaques are cardinal histopathological hallmarks of Alzheimer's disease, fundamental to the amyloid cascade hypothesis of the disease, which posits cerebral Aβ accumulation as a crucial early player in disease pathogenesis, ultimately leading to neurodegeneration and dementia.1 If the amyloid hypothesis is correct, then inhibition of cerebral Aβ accumulation could benefit patients with Alzheimer's disease.

The β secretase, referred to as β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), is the enzyme that initiates Aβ production by cleaving the extracellular domain of APP. Inhibitors of BACE1 are being considered at present for their potential to lower cerebral Aβ concentrations and to treat and prevent Alzheimer's disease. Although several promising BACE1 inhibitors are being tested in human clinical trials, many questions remain about the safety of these drugs, the optimum level of BACE1 inhibition to achieve efficacy without unacceptable side-effects, and the stage of disease at which to treat for greatest therapeutic gain. Here, we review the potential of therapeutic BACE1 inhibition for Alzheimer's disease at a crucial time in the search for effective approaches to treatment and prevention.

Section snippets

Amyloid β and Alzheimer's disease

In the brain, Aβ is predominantly produced by neurons, although other cell types, including astrocytes and other glia, also generate Aβ especially under stress conditions that induce glial activation, as occurs in Alzheimer's disease. Aβ is formed by the sequential proteolysis of the type 1 membrane protein APP (figure 1A). APP is first cleaved by the β-secretase enzyme to yield a membrane-bound C-terminal fragment called C99.2 A second enzyme named γ secretase, composed of four transmembrane

BACE1

In view of the role of Aβ in Alzheimer's disease pathogenesis, the molecular cloning of the secretase enzymes became a major goal for their value as drug targets. The characteristics of Aβ production and secretase activities in cultured cells allowed the development of cell-based assays for secretase identification. Five groups independently reported the molecular cloning of the β-secretase enzyme, variously named β-site APP cleaving enzyme (BACE), Asp2, and memapsin 2.12, 13, 14, 15, 16

BACE1 knockout mice

To unequivocally show in vivo that BACE1 is the β secretase implicated in Alzheimer's disease, several groups used gene targeting strategies to generate BACE1 knockout (−/−) mice.24, 25, 26, 27 These mice were initially reported to be viable and fertile with no overt phenotype, and to have normal gross morphology and behaviour, tissue histology, and blood cell and clinical chemistry characteristics, implying that therapeutic inhibition of BACE1 might be free of mechanism-based side-effects. The

BACE1 inhibitor drugs for Alzheimer's disease

In view of the strong in-vivo and in-vitro validation of BACE1 as the major β-secretase enzyme in the brain, intense efforts are underway in both academia and industry to develop small-molecule inhibitors of BACE1. Initial inhibitors were non-cleavable peptide-based transition state analogues modelled after the β-secretase cleavage site of APP.14, 60 In vitro, these sizable peptidomimetic molecules are potent BACE1 inhibitors, mainly because the large open BACE1 active site evolved to bind

Outstanding questions

The long-awaited initiation of clinical trials for BACE1 inhibitors is a promising development and raises hopes that disease-modifying therapies involving BACE1 inhibition for Alzheimer's disease are within reach. However, several crucial questions concerning therapeutic goals and outcomes of these trials remain.

Conclusions and future developments

As the enzyme that initiates Aβ production, BACE1 is a key therapeutic target for Alzheimer's disease. The Ala673Thr mutation and BACE1 gene knockout reduce Aβ generation, strongly suggesting that BACE1 inhibition should prove effective for Alzheimer's disease. Although BACE1−/− mice are viable and fertile, they display many complex neurological phenotypes (table 1), which imply that BACE1 inhibitor drugs could cause mechanism-based side-effects, such as hypomyelination, seizures, axon guidance

Search strategy and selection criteria

The sources of information in this Review were mainly peer-reviewed primary research journal articles and secondary review articles that were identified on PubMed with the search terms “beta-secretase and Alzheimer's disease”, “BACE and Alzheimer's disease”, “BACE inhibitor”, and “BACE inhibitor clinical trial” from Jan 1, 1990, to Oct 24, 2013. In a few instances, information about the status of BACE1 inhibitor clinical trials was obtained from statements on company websites. Criteria used to

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