期刊
NEURON
卷 54, 期 5, 页码 721-737出版社
CELL PRESS
DOI: 10.1016/j.neuron.2007.05.012
关键词
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资金
- NIA NIH HHS [R01 AG033016, R01 AG025952, R01 AG025952-01A2, 1R01AG025952, R01 AG025888] Funding Source: Medline
- NIMH NIH HHS [R37 MH060009, K12 MH069281, K12 MH069281-04, 1K12MH069281, R37 MH060009-08, 1R37MH60009] Funding Source: Medline
beta-site APP-cleaving enzyme (BACE) is required for production of the Alzheimer's disease (AD)-associated AD protein. BACE levels are elevated in AD brain, and increasing evidence reveals BACE as a stress-related protease that is upregulated following cerebral ischemia. However, the molecular mechanism responsible is unknown. We show that increases in BACE and beta-secretase activity are due to posttranslational stabilization following caspase activation. We also found that during cerebral ischemia, levels of GGA3, an adaptor protein involved in BACE trafficking, are reduced, while BACE levels are increased. RNAi silencing of GGA3 also elevated levels of BACE and AD. Finally, in AD brain samples, GGA3 protein levels were significantly decreased and inversely correlated with increased levels of BACE. In summary, we have elucidated a GGA3-dependent mechanism regulating BACE levels and beta-secretase activity. This mechanism may explain increased cerebral levels of BACE and AD following cerebral ischemia and existing in AD.
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