BACE1: The β-secreiase enzyme in Alzheimer's disease

Robert Vassar*

*Corresponding author for this work

Research output: Contribution to journalReview article

244 Scopus citations

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 β 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.

Original languageEnglish (US)
Pages (from-to)105-113
Number of pages9
JournalJournal of Molecular Neuroscience
Volume23
Issue number1-2
DOIs
StatePublished - Apr 1 2004

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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