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Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.

Authors: Tesco, Giuseppina  Koh, Young Ho  Kang, Eugene L  Cameron, Andrew N  Das, Shinjita  Sena-Esteves, Miguel  Hiltunen, Mikko  Yang, Shao-Hua  Zhong, Zhenyu  Shen, Yong  Simpkins, James W  Tanzi, Rudolph E 
Citation: Tesco G, etal., Neuron. 2007 Jun 7;54(5):721-37. doi: 10.1016/j.neuron.2007.05.012.
Pubmed: (View Article at PubMed) PMID:17553422
DOI: Full-text: DOI:10.1016/j.neuron.2007.05.012

Beta-site APP-cleaving enzyme (BACE) is required for production of the Alzheimer's disease (AD)-associated Abeta 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 Abeta. 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 Abeta following cerebral ischemia and existing in AD.

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CRRD Object Information
CRRD ID: 13825190
Created: 2018-11-21
Species: All species
Last Modified: 2018-11-21
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.