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Thomas, Douglas D.

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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1437-4315
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Volume 391, Issue 8 (Aug 2010)

Issues

Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions

David W. Klaver
  • Menzies Research Institute, University of Tasmania, Hobart, Tasmania 7000, Australia
  • Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
/ Matthew C.J. Wilce
  • Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
/ Hao Cui
  • Menzies Research Institute, University of Tasmania, Hobart, Tasmania 7000, Australia
  • Department of Pharmacy, University of Tasmania, Hobart, Tasmania 7000, Australia
/ Amos C. Hung
  • Menzies Research Institute, University of Tasmania, Hobart, Tasmania 7000, Australia
/ Robert Gasperini
  • Menzies Research Institute, University of Tasmania, Hobart, Tasmania 7000, Australia
/ Lisa Foa
  • Menzies Research Institute, University of Tasmania, Hobart, Tasmania 7000, Australia
/ David H. Small
  • Menzies Research Institute, University of Tasmania, Hobart, Tasmania 7000, Australia
  • Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
Published Online: 2010-05-19 | DOI: https://doi.org/10.1515/bc.2010.089

Abstract

Alzheimer's disease (AD) is characterized by the extracellular deposition of the β-amyloid protein (Aβ). Aβ is a fragment of a much larger precursor protein, the amyloid precursor protein (APP). Sequential proteolytic cleavage of APP by β-secretase and γ-secretase liberates Aβ from APP. The aspartyl protease BACE1 (β-site APP-cleaving enzyme 1) catalyses the rate-limiting step in the production of Aβ, and as such it is considered to be a major target for drug development in Alzheimer's disease. However, the development of a BACE1 inhibitor therapy is problematic for two reasons. First, BACE1 has been found to have important physiological roles. Therefore, inhibition of the enzyme could have toxic consequences. Second, the active site of BACE1 is relatively large, and many of the bulky compounds that are needed to inhibit BACE1 activity are unlikely to cross the blood-brain barrier. This review focuses on the structure BACE1, current therapeutic strategies based on developing active-site inhibitors, and new approaches to therapy involving targeting the expression or post-translational regulation of BACE1.

Keywords: Alzheimer's disease; amyloid; β-secretase; β-site APP cleaving enzyme (BACE); protease; therapy

About the article

Corresponding author


Received: 2010-02-15

Accepted: 2010-04-14

Published Online: 2010-05-19

Published in Print: 2010-08-01



Citation Information: Biological Chemistry, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/bc.2010.089. Export Citation

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