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β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE

  • Author(s): Vassar, R
  • Bennett, BD
  • Babu-Khan, S
  • Kahn, S
  • Mendiaz, EA
  • Denis, P
  • Teplow, DB
  • Ross, S
  • Amarante, P
  • Loeloff, R
  • Luo, Y
  • Fisher, S
  • Fuller, J
  • Edenson, S
  • Lile, J
  • Jarosinski, MA
  • Biere, AL
  • Curran, E
  • Burgess, T
  • Louis, JC
  • Collins, F
  • Treanor, J
  • Rogers, G
  • Citron, M
  • et al.
Abstract

Cerebral deposition of amyloid β peptide (Aβ) is an early and critical feature of Alzheimer's disease. Aβ generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: β- secretase and γ-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of β- secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of β- secretase cleavage products, and these were cleaved exactly and only at known β-secretase positions. Antisense inhibition of endogenous BACE messenger RHA decreased the amount of β-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as β-secretase. Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for β-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.

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