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Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
journal contribution
posted on 2023-05-17, 03:18 authored by Klaver, DW, Wilce, MCJ, Cui, H, Hung, AC, Robert GasperiniRobert Gasperini, Lisa FoaLisa Foa, David SmallDavid SmallAlzheimer’s disease (AD) is characterized by the extracellular deposition of the b-amyloid protein (Ab). Ab is a fragment of a much larger precursor protein, the amyloid precursor protein (APP). Sequential proteolytic cleavage of APP by b-secretase and g-secretase liberates Ab from APP. The aspartyl protease BACE1 (b-site APP-cleaving enzyme 1) catalyses the rate-limiting step in the production of Ab, 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.
History
Publication title
Biological Chemistry: Official Journal of The German Society for Biochemistry and Molecular BiologyVolume
391Issue
8Pagination
849-859ISSN
1431-6730Department/School
Menzies Institute for Medical ResearchPublisher
Walter De Gruyter & CoPlace of publication
Genthiner Strasse 13, Berlin, Germany, D-10785Rights statement
Copyright © 2010 Walter de Gruyter.Repository Status
- Restricted