期刊
EMBO MOLECULAR MEDICINE
卷 4, 期 3, 页码 171-179出版社
WILEY-BLACKWELL
DOI: 10.1002/emmm.201100195
关键词
Alzheimer disease; BACE1; BRI2; familial Danish dementia; mouse models
资金
- Alzheimer's Association [IIRG-09-129984]
- Edward N and Della L. Thome Memorial Foundation
- National Institutes of Health (NIH) [R01AG033007]
A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-beta precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by beta-secretase rescues synaptic/memory deficits in a mouse model of FDD. beta-cleavage of APP yields amino-terminal-soluble APP beta (sAPP beta) and beta-carboxyl-terminal fragments (beta-CTF). Processing of beta-CTF by gamma-secretase releases amyloid-beta (A beta), which is assumed to cause AD. However, inhibition of gamma-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPP beta and/or beta-CTF, rather than A beta, are the toxic species causing dementia, and indicate that reducing beta-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-A beta therapies in humans advise against targeting gamma-secretase cleavage of APP and/or A beta.
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