Aβ induces PUMA activation: a new mechanism for Aβ-mediated neuronal apoptosis
Jie Feng1, Chengbo Meng1, Da Xing1
1MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.
Abstract:
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-β (Aβ) deposition causes neurotoxicity. The regulation of PUMA during Aβ-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 Aβ. PUMA knockdown protected the neurons against Aβ-induced apoptosis. Furthermore, besides p53, PUMA transactivation was also regulated by forkhead box O3a through p53-independent manner following Aβ 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 Aβ-induced neuronal apoptosis. Together, we demonstrated that PUMA activation involved in Aβ-induced apoptosis, representing a drug target to antagonize AD progression.
Insights
PUMA activation drives neuronal apoptosis in Alzheimer's disease (AD) models. Inhibiting PUMA may offer a new therapeutic strategy to combat AD progression by protecting neurons from amyloid-beta toxicity.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- p53 upregulated modulator of apoptosis (PUMA) is crucial for apoptosis and cancer therapy.
- Excessive apoptosis contributes to neurodegenerative disorders like Alzheimer's disease (AD).
- Amyloid-beta (Aβ) deposition in AD causes neurotoxicity, but PUMA's role is unclear.
Purpose of the Study:
- To investigate the role and regulation of PUMA in Aβ-induced neuronal apoptosis.
- To elucidate the molecular mechanisms by which PUMA mediates Aβ neurotoxicity.
- To assess PUMA as a potential therapeutic target for AD.
Main Methods:
- Examined PUMA expression in AD transgenic mouse models and Aβ-treated hippocampal neurons.
- Utilized PUMA knockdown to assess its protective effects against Aβ-induced apoptosis.
- Investigated PUMA regulation by p53 and forkhead box O3a (FOXO3a).
- Analyzed the downstream apoptotic pathway involving caspase-8, Bid, and Bax.
Main Results:
- PUMA expression was significantly upregulated in AD models and by Aβ treatment.
- PUMA knockdown conferred neuroprotection against Aβ-induced apoptosis.
- Aβ treatment induced p53-independent PUMA transactivation via FOXO3a.
- PUMA promoted apoptosis by activating caspase-8, leading to Bid cleavage and Bax translocation.
Conclusions:
- PUMA activation is a key mediator of Aβ-induced neuronal apoptosis.
- A novel PUMA-dependent pathway for Bax activation in AD was identified.
- Targeting PUMA represents a promising therapeutic strategy for Alzheimer's disease.
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