Journal of Molecular Neuroscience

, Volume 23, Issue 1, pp 105–113

Bace 1

The β-secretase enzyme in alzheimer’s disease
Review Article

DOI: 10.1385/JMN:23:1-2:105

Cite this article as:
Vassar, R. J Mol Neurosci (2004) 23: 105. doi:10.1385/JMN:23:1-2:105

Abstract

Data that have accumulated for well over a decade have implicated the β-amyloid (Aβ) peptide as a central player in the pathogenesis of Alzheimer’s disease (AD). Amyloid plaques, composed primarily of Aβ progressively form in the brains of AD patients, and mutations in three genes (amyloid precursor protein [APP] and presenilin 1 and 2 [PS1 and PS2]) cause early-onset familial AD (FAD) by directly increasing production of the toxic, plaque-promoting Aβ42 peptide. Given the strong association between Aβ and AD, it is likely that therapeutic strategies to lower the levels of Aβ in the brain should prove beneficial for the treatment of AD. One such strategy could involve inhibiting the enzymes that generate Aβ. Aβ is a product of catabolism of the large type-I membrane protein APP. Two proteases, called β- and γ-secretase, endoproteolyze APP to liberate the Aβ peptide. Recently, the molecules responsible for these proteolytic activities have been identified. Several lines of evidence suggest that the PS1 and PS2 proteins are γ-secretase, and the identity of β-secretase has been shown to be the novel transmembrane aspartic protease, β-site APP-cleaving enzyme 1 (BACE1; also called Asp2 and memapsin 2). BACE2, a protease homologous to BACE1, was also identified, and together the two enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the functional properties of β-secretase, and as the key enzyme that initiates the formation of Aβ, BACE1 is an attractive drug target for AD. This review discusses the identification and initial characterization of BACE1 and BACE2, and summarizes recent studies of BACE1 knockout mice that have validated BACE1 as the authentic β-secretase in vivo.

Index Entries

Alzheimer’s disease β-amyloid Aβ peptide amyloid precursor protein β-secretase BACE1 BACE2 β-site APP clearing enzyme 

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  1. 1.Department of Cell and Molecular BiologyThe Feinberg School of Medicine, Northwestern UniversityChicago

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