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  • BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β.

BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β.

Cell death discovery (2021-11-17)
Akash Saha, Suraiya Saleem, Ramesh Kumar Paidi, Subhas C Biswas
摘要

Alzheimer's disease (AD) is characterized by accumulation of senile amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles causing progressive loss of synapse and neuronal death. Out of the various neuron death modalities, autophagy and apoptosis are reported to be the major death paradigms in AD. However, how these two processes lead to neuronal loss is still inconspicuous. Here we report that under Aβ toxicity, aberrant autophagy is induced with inefficient autophagic flux in neurons. Simultaneous activation of both autophagy and apoptosis are seen in primary cortical neurons as well as in transgenic mice brains. We found that induction of autophagy by rapamycin is detrimental for neurons; whereas downregulation of Beclin1, an important autophagy inducing protein, provides significant protection in Aβ treated neuronal cells by blocking cytochrome-c release from the mitochondria. We further report that downregulation of Puma, a BH3-only pro-apoptotic protein, inhibits the induction of aberrant autophagy and also ameliorates the autophagy flux under the influence of Aβ. Notably, stereotactic administration of shRNAs against Puma and Beclin1 in adult Aβ-infused rat brains inhibits both apoptotic and autophagic pathways. The regulation of both of the death processes is brought about by the direct interaction between Puma and Beclin1 upon Aβ treatment. We conclude that both Beclin1 and Puma play essential roles in the neuronal death caused by the induction of aberrant autophagy in AD and targeting their interaction could be vital to understand the crosstalk of autophagy and apoptosis as well as to develop a potential therapeutic strategy in AD.

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抗-β-肌动蛋白−过氧化物酶抗体,小鼠单克隆 小鼠抗, clone AC-15, purified from hybridoma cell culture
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半胱天冬酶抑制剂I, Z-VAD-FMK, CAS 187389-52-2, is a cell-permeable, irreversible, pan-caspase inhibitor.