A? induces PUMA activation: a new mechanism for A?-mediated neuronal apoptosis.

p53 upregulated modulator of apoptosis (PUMA) is a promising tumor therapy target because it elicits apoptosis and profound sensitivity to radiation and chemotherapy. However, inhibition of PUMA may be beneficial for curbing excessive apoptosis associated with neurodegenerative disorders. Alzheimer's disease (AD) is a representative neurodegenerative disease in which amyloid-? (A?) ...
deposition causes neurotoxicity. The regulation of PUMA during A?-induced neuronal apoptosis remains poorly understood. Here, we reported that PUMA expression was significantly increased in the hippocampus of transgenic mice models of AD and hippocampal neurons in response to A?. PUMA knockdown protected the neurons against A?-induced apoptosis. Furthermore, besides p53, PUMA transactivation was also regulated by forkhead box O3a through p53-independent manner following A? treatment. Notably, PUMA contributed to neuronal apoptosis through competitive binding of apoptosis repressor with caspase recruitment domain to activate caspase-8 that cleaved Bid into tBid to accelerate Bax mitochondrial translocation, revealing a novel pathway of Bax activation by PUMA to mediate A?-induced neuronal apoptosis. Together, we demonstrated that PUMA activation involved in A?-induced apoptosis, representing a drug target to antagonize AD progression.
Mesh Terms:
Alzheimer Disease, Amyloid beta-Peptides, Animals, Apoptosis, Apoptosis Regulatory Proteins, Caspase 8, Cells, Cultured, Forkhead Box Protein O3, Forkhead Transcription Factors, Gene Expression Regulation, Developmental, Hippocampus, Humans, Mice, Transgenic, Molecular Targeted Therapy, Neurons, Transcriptional Activation, Tumor Suppressor Proteins, bcl-2-Associated X Protein
Neurobiol. Aging
Date: Feb. 01, 2015
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