Beta-Secretase: Structure, Function, and Evolution

Author(s): Chitra Venugopal, Christina M. Demos, K. S. Jagannatha Rao, Miguel A. Pappolla, Kumar Sambamurti

Journal Name: CNS & Neurological Disorders - Drug Targets
Formerly Current Drug Targets - CNS & Neurological Disorders

Volume 7 , Issue 3 , 2008

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The most popular current hypothesis is that Alzheimers disease (AD) is caused by aggregates of the amyloid peptide (Aβ), which is generated by cleavage of the Aβ protein precursor (APP) by β-secretase (BACE-1) followed by γ- secretase. BACE-1 cleavage is limiting for the production of Aβ, making it a particularly good drug target for the generation of inhibitors that lower Aβ. A landmark discovery in AD was the identification of BACE-1 (a.k.a. Memapsin-2) as a novel class of type I transmembrane aspartic protease. Although BACE-2, a homologue of BACE-1, was quickly identified, follow up studies using knockout mice demonstrated that BACE-1 was necessary and sufficient for most neuronal Aβ generation. Despite the importance of BACE-1 as a drug target, development has been slow due to the incomplete understanding of its function and regulation and the difficulties in developing a brain penetrant drug that can specifically block its large catalytic pocket. This review summarizes the biological properties of BACE-1 and attempts to use phylogenetic perspectives to understand its function. The article also addresses the challenges in discovering a selective druglike molecule targeting novel mechanisms of BACE-1 regulation.

Keywords: BACE-1, Secretase, Memapsin, Alzheimer, Amyloid, Aspartyl protease

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Article Details

Year: 2008
Page: [278 - 294]
Pages: 17
DOI: 10.2174/187152708784936626
Price: $65

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