β-secretase (BACE) as a drug target for Alzheimer's disease

Robert Vassar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

185 Scopus citations

Abstract

Evidence suggests that the β-amyloid peptide (Aβ) is central to the pathophysiology of Alzheimer's Disease (AD). Amyloid plaques, primarily composed of Aβ, progressively develop in the brains of AD patients, and mutations in three genes (APP, PS1, and PS2) cause early on-set familial AD (FAD) by increasing synthesis of the toxic Aβ42 peptide. Given the strong association between Aβ and AD, therapeutic strategies to lower the concentration of Aβ in the brain should prove beneficial for the treatment of AD. Aβ is a proteolytic product of the large TypeI membrane protein, amyloid precursor protein (APP). Two proteases, called β- and γ-secretase, cleave APP to generate the Aβ peptide. For over a decade, the molecular identities of these proteases were unknown. Recently, the γ-secretase has been tentatively identified as the presenilin proteins, PS1 and PS2, and the β-secretase has been shown to be the novel transmembrane aspartic protease, β-site APP Cleaving Enzyme 1 (BACE1; also called Asp2 and memapsin2). BACE2, a novel protease homologous to BACE1, was also identified, and the two BACE enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the properties of the 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 our current understanding of BACE1 post-translational processing and intracellular trafficking. Finally, recent studies of BACE1 knockout mice, the BACE1 X-ray structure, and implications for BACE1 drug development will be discussed.

Original languageEnglish (US)
Pages (from-to)1589-1602
Number of pages14
JournalAdvanced Drug Delivery Reviews
Volume54
Issue number12
DOIs
StatePublished - Dec 7 2002

Keywords

  • APP Processing
  • Alzheimer's disease
  • Aβ Peptide
  • BACE
  • β-Amyloid
  • β-Secretase

ASJC Scopus subject areas

  • Pharmaceutical Science

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