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Abstract：
Recent researches suggest that autophagic degradation declines with age, and this leads to an accumulation of damage that contributes to age-related cellular dysfunction. Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) shows therapeutic potential for cerebral ischemia in young-adult animals. This study investigated the role of NMNAT1 in focal cerebral ischemia in aged rats with a focus on neuronal autophagy. Focal cerebral ischemia was induced in aged rats by middle cerebral artery occlusion (MCAO). NMNAT1 levels in the peri-infarct penumbra increased at 12 and 24 h after ischemia in aged rats. Knockdown of NMNAT1 significantly increased infarct volume, whereas overexpression of NMNAT1 reduced ischemia-induced cerebral injuries in aged rats with acute ischemic stroke. Meanwhile, lentiviral overexpression of NMNAT1 increased autophagy, reduced the phosphorylation of mammalian target of rapamycin (mTOR), and enhanced the sirtuin 1 (SIRT1) protein level. In cultured cortical neurons, SIRT1 regulated the mTOR-mediated autophagy upon oxygen-glucose deprivation (OGD) stress and the effect of NMNAT1 on autophagy was blocked in cultured SIRT1-knockout neurons. Furthermore, autophagy inhibitor 3-methyladenine (3-MA) partly abolished the neuroprotection induced by NMNAT1 overexpression. The results suggest NMNAT1 protects against acute ischemic stroke in aged rats by inducing autophagy via regulating the SIRT1/mTOR pathway.
摘要：
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