期刊
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS
卷 7, 期 3, 页码 278-294出版社
BENTHAM SCIENCE PUBL
DOI: 10.2174/187152708784936626
关键词
BACE-1; Secretase; Memapsin; Alzheimer; Amyloid; Aspartyl protease
资金
- NIA NIH HHS [R01 AG023055-02, R01 AG023055-01A1, R01 AG022103, AG022103, R01 AG023055-03, R01 AG023055-05, R01 AG023055, R01 AG023055-04, AG023055] Funding Source: Medline
- NATIONAL INSTITUTE ON AGING [R01AG023055, R01AG022103] Funding Source: NIH RePORTER
The most popular current hypothesis is that Alzheimer's disease (AD) is caused by aggregates of the amyloid peptide (A beta) which is generated by cleavage of the A beta protein precursor (APP) by beta-secretase (BACE-1) followed by gamma-secretase. BACE-1 cleavage is limiting for the production of A beta making it a particularly good drug target for the generation of inhibitors that lower A beta. 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 A beta 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 drug-like molecule targeting novel mechanisms of BACE-1 regulation.
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