Journal
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS
Volume 7, Issue 3, Pages 278-294Publisher
BENTHAM SCIENCE PUBL
DOI: 10.2174/187152708784936626
Keywords
BACE-1; Secretase; Memapsin; Alzheimer; Amyloid; Aspartyl protease
Categories
Funding
- 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
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available