Depletion of GGA3 Stabilizes BACE and Enhances β-Secretase Activity
Copyright policy )Depletion of GGA3 Stabilizes BACE and Enhances β-Secretase Activity
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.
- Banner Health United States
- Harvard University United States
- Massachusetts General Hospital United States
- University of North Texas Health Science Center United States
- Center for Neurosciences United States
Amyloid beta-Peptides, ADP-Ribosylation Factors, Neuroscience(all), Molecular Sequence Data, HUMDISEASE, Brain, Down-Regulation, MOLNEURO, Brain Ischemia, Rats, Adaptor Proteins, Vesicular Transport, Amyloid beta-Protein Precursor, Mice, Dogs, Alzheimer Disease, Animals, Aspartic Acid Endopeptidases, Humans, CELLBIO, Cattle, RNA Interference, Amyloid Precursor Protein Secretases, Protein Processing, Post-Translational, Cells, Cultured
Amyloid beta-Peptides, ADP-Ribosylation Factors, Neuroscience(all), Molecular Sequence Data, HUMDISEASE, Brain, Down-Regulation, MOLNEURO, Brain Ischemia, Rats, Adaptor Proteins, Vesicular Transport, Amyloid beta-Protein Precursor, Mice, Dogs, Alzheimer Disease, Animals, Aspartic Acid Endopeptidases, Humans, CELLBIO, Cattle, RNA Interference, Amyloid Precursor Protein Secretases, Protein Processing, Post-Translational, Cells, Cultured
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