Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus.
Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus.
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中年晚期的二甲双胍治疗可通过减轻小胶质细胞活化和增强海马自噬来改善认知功能。
DOI：
10.1111/acel.13277
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发表时间：
2021-03
期刊：
影响因子：
7.8
通讯作者：
Shetty AK
中科院分区：
文献类型：
--
作者：
Kodali M;Attaluri S;Madhu LN;Shuai B;Upadhya R;Gonzalez JJ;Rao X;Shetty AK
在中年晚期接受10周二甲双胍治疗可有效改善老年人的认知功能。二甲双胍治疗后认知功能的改善与海马效应、腺苷一磷酸活化蛋白激酶（AMPK）激活、哺乳动物雷帕霉素靶蛋白（mTOR）信号传导和老年海马自噬增加有关。结果表明，二甲双胍治疗中年导致老年人更好的认知功能。 二甲双胍是一种广泛用于治疗糖尿病的药物，可以延长几个物种的寿命。Metabolic还有望减缓与年龄相关的认知障碍。然而，二甲双胍作为抗衰老药物的治疗用途尚未被接受，因为动物和人体研究结果相互矛盾。我们研究了中年晚期二甲双胍治疗对老年认知功能的影响。18月龄雄性C57 BL 6/J小鼠接受二甲双胍或未接受二甲双胍治疗10周。一系列行为测试显示，接受二甲双胍的动物认知功能得到改善。这些发现从更好的模式分离、物体定位和识别记忆功能的能力中显而易见。小胶质细胞的定量显示，二甲双胍处理降低了病理性小胶质细胞簇的发生率，并将小胶质细胞交替活化为M2表型，在海马中显示出高度分枝的过程。二甲双胍治疗似乎也减少了星形胶质细胞肥大。其他分析表明，中年晚期二甲双胍治疗增加了腺苷酸活化蛋白激酶的活化，降低了促炎细胞因子水平和雷帕霉素信号传导的哺乳动物靶点，并增强了海马体中的自噬。然而，二甲双胍治疗没有改变海马中的神经发生或突触，这意味着二甲双胍改善的认知功能不涉及增强的神经发生或新突触发生。研究结果提供了新的证据，表明在中年晚期开始二甲双胍治疗有望改善老年人的认知功能。调节小胶质细胞、促炎细胞因子和自噬似乎是二甲双胍促进老年脑功能获益的机制。
Ten weeks of metformin treatment in late middle age is efficacious for improving cognitive function in the old age. Improved cognitive function following metformin treatment was linked with antiinflammatory effects, the activation of adenosine monophosphate‐activated protein kinase (AMPK), the mammalian target of rapamycin (mTOR) signaling, and increased autophagy in the aged hippocampus. The results suggest that metformin therapy in middle age leads to better cognitive function in old age. Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age‐related cognitive impairment. However, metformin's therapeutic use as an anti‐aging drug is yet to be accepted because of conflicting animal and human studies results. We examined the effects of metformin treatment in late middle age on cognitive function in old age. Eighteen‐month‐old male C57BL6/J mice received metformin or no treatment for 10 weeks. A series of behavioral tests revealed improved cognitive function in animals that received metformin. Such findings were evident from a better ability for pattern separation, object location, and recognition memory function. Quantification of microglia revealed that metformin treatment reduced the incidence of pathological microglial clusters with alternative activation of microglia into an M2 phenotype, displaying highly ramified processes in the hippocampus. Metformin treatment also seemed to reduce astrocyte hypertrophy. Additional analysis demonstrated that metformin treatment in late middle age increased adenosine monophosphate‐activated protein kinase activation, reduced proinflammatory cytokine levels, and the mammalian target of rapamycin signaling, and enhanced autophagy in the hippocampus. However, metformin treatment did not alter neurogenesis or synapses in the hippocampus, implying that improved cognitive function with metformin did not involve enhanced neurogenesis or neosynaptogenesis. The results provide new evidence that metformin treatment commencing in late middle age has promise for improving cognitive function in old age. Modulation of microglia, proinflammatory cytokines, and autophagy appear to be the mechanisms by which metformin facilitated functional benefits in the aged brain.
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影响因子：
4.3
作者：
Gandy K;Kim S;Sharp C;Dindo L;Maletic-Savatic M;Calarge C
通讯作者：
Calarge C
影响因子：
2
作者：
Gabryel, Bozena;Liber, Sebastian
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Liber, Sebastian
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20.1
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3.9
作者：
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通讯作者：
Giovannini, Maria Grazia
影响因子：
4
作者：
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Tsai, Hsin-Ni