Aβ induces PUMA activation: a new mechanism for Aβ-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-beta (A beta) deposition causes neurotoxicity. The regulation of PUMA during A beta-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 beta. PUMA knockdown protected the neurons against A beta-induced apoptosis. Furthermore, besides p53, PUMA transactivation was also regulated by forkhead box O3a through p53-independent manner following A beta 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 beta-induced neuronal apoptosis. Together, we demonstrated that PUMA activation involved in A beta-induced apoptosis, representing a drug target to antagonize AD progression. (C) 2015 Elsevier Inc. All rights reserved.