Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis.
Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis.
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二甲双胍通过促进脑血管生成和神经发生来改善老年小鼠的认知能力
DOI：
10.18632/aging.103693
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发表时间：
2020-09-16
期刊：
影响因子：
--
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Zhu X;Shen J;Feng S;Huang C;Liu Z;Sun YE;Liu H
脑微血管对于维持正常的脑功能至关重要。与年龄相关的神经发生和认知功能的下降伴随着血流量的减少和神经干细胞（NSC）数量的下降。在这里，我们报告说，尾静脉注射二甲双胍以剂量依赖的方式增强了老年小鼠的认知能力，但没有增强年轻小鼠的认知能力。此外，二甲双胍在体内和体外恢复了脑血流量和脑血管密度，并促进了室管膜下区/脑室下区的神经源性潜力。 RNA-Seq结果表明，二甲双胍可以增强血液中的糖酵解，二甲双胍治疗的小鼠海马组织中糖酵解途径中酶的相对mRNA表达增加。从机制上讲，3-磷酸甘油醛脱氢酶（GAPDH）是糖酵解途径中的关键酶，可能有助于 NSC 的血管生成和神经生成潜力。有趣的是，对不同年龄段人群外周血单个核细胞的检测发现，GAPDH mRNA表达量随着年龄的增长逐渐下降，而其表达水平与认知水平呈正相关。我们的结果表明，二甲双胍代表了一种通过增强糖酵解和促进神经血管生成在老年小鼠大脑中招募 NSC 的候选药理学方法，这一策略可能对人类抗衰老具有治疗价值。图解摘要
The cerebral microvasculature is essential for preservation of normal cerebral function. Age-related decreases of neurogenesis and cognitive function are accompanied by reduced blood flow and a decline in neural stem cell (NSC) number. Here, we report that metformin administered by tail vein injection enhanced cognition in aged but not young mice in a dose-dependent manner. Further, metformin restored cerebral blood flow and brain vascular density and promoted neurogenic potential of the subependymal zone/subventricular zone both in vivo and in vitro. RNA-Seq result indicated that metformin could enhance glycolysis in blood, with an increase in relative mRNA expression of the enzyme in the glycolysis pathway from hippocampal tissue of metformin-treated mice. Mechanistically, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key enzyme in the glycolysis pathway, may contribute to angiogenic and neurogenic potentials of NSCs. Interestingly, examination of peripheral blood mononuclear cells from people of various ages showed that mRNA expression of GAPDH gradually decreased with age, while its expression level positively correlated with cognitive levels. Our results indicate that metformin represents a candidate pharmacological approach for recruitment of NSCs in aged mouse brain by enhancing glycolysis and promoting neurovascular generation, a strategy that might be of therapeutic value for anti-aging in humans. Graphical Abstract
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影响因子：
3
作者：
Bensalem J;Servant L;Alfos S;Gaudout D;Layé S;Pallet V;Lafenetre P
通讯作者：
Lafenetre P
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21.3
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El-Mir, MY;Nogueira, V;Leverve, X
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Leverve, X
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Li, Wenjun;Chaudhari, Kiran;Yang, Shao-Hua
通讯作者：
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影响因子：
7.7
作者：
Shestov AA;Liu X;Ser Z;Cluntun AA;Hung YP;Huang L;Kim D;Le A;Yellen G;Albeck JG;Locasale JW
通讯作者：
Locasale JW