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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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