Metformin treatment ameliorates diabetes-associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1.
Metformin treatment ameliorates diabetes-associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1.
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DOI：
10.1002/2211-5463.12436
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发表时间：
2018-07
期刊：
影响因子：
2.6
通讯作者：
Taguchi A
中科院分区：
文献类型：
--
作者：
Tanokashira D;Kurata E;Fukuokaya W;Kawabe K;Kashiwada M;Takeuchi H;Nakazato M;Taguchi A
成人海马神经发生与年龄相关的减少与认知障碍相关。糖尿病是一种慢性全身性疾病，对成体神经干细胞和海马记忆功能产生负面影响。尽管人们越来越关注糖尿病药物在神经异常中的潜在作用，但它们对神经发生和认知功能进行性恶化的影响尚不清楚。在这里，我们发现衰老和糖尿病的结合导致小鼠海马神经发生显著减少，同时伴有记忆障碍和神经炎症升高。二甲双胍（一种双胍类抗糖尿病药物）长期治疗可促进细胞增殖和神经元分化，抑制衰老和糖尿病相关的小胶质细胞激活，这与内稳态神经发生有关，从而增强了中年糖尿病小鼠的海马神经发生。虽然二甲双胍慢性治疗不能从高血糖中恢复，这是中年糖尿病小鼠糖尿病的一个关键特征，但它可以改善海马依赖的空间记忆功能，同时增加海马中选择性丝氨酸残基上腺苷单磷酸活化蛋白激酶（AMPK）、非典型蛋白激酶C ζ (aPKC ζ)和胰岛素受体底物1 （IRS1）的磷酸化。我们的研究结果表明，通过长期二甲双胍刺激AMPK， aPKC ζ/λ和IRS1丝氨酸位点磷酸化的信号网络有助于对海马神经发生和认知功能的神经保护作用，而不依赖于降糖作用。
Age‐related reduction in adult hippocampal neurogenesis is correlated with cognitive impairment. Diabetes is a chronic systemic disease that negatively affects adult neural stem cells and memory functions in the hippocampus. Despite growing concern regarding the potential role of diabetic drugs in neural abnormalities, their effects on progressive deterioration of neurogenesis and cognitive functions remain unknown. Here, we show that the combination of aging and diabetes in mice causes a marked decrease in hippocampal neurogenesis along with memory impairment and elevated neuroinflammation. Prolonged treatment with metformin, a biguanide antidiabetic medication, promotes cell proliferation and neuronal differentiation and inhibits aging‐ and diabetes‐associated microglial activation, which is related to homeostatic neurogenesis, leading to enhanced hippocampal neurogenesis in middle‐aged diabetic mice. Although chronic therapy with metformin fails to achieve recovery from hyperglycemia, a key feature of diabetes in middle‐aged diabetic mice, it improves hippocampal‐dependent spatial memory functions accompanied by increased phosphorylation of adenosine monophosphate‐activated protein kinase (AMPK), atypical protein kinase C ζ (aPKC ζ), and insulin receptor substrate 1 (IRS1) at selective serine residues in the hippocampus. Our findings suggest that signaling networks acting through long‐term metformin‐stimulated phosphorylation of AMPK, aPKC ζ/λ, and IRS1 serine sites contribute to neuroprotective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect.
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影响因子：
6.3
作者：
Calvo-Ochoa, Erika;Hernandez-Ortega, Karina;Arias, Clorinda
通讯作者：
Arias, Clorinda
长期鼻内胰岛素治疗可改善链脲佐菌素诱导的阿尔茨海默病大鼠模型中的认知障碍、tau 蛋白过度磷酸化和小胶质细胞激活
影响因子：
4.6
作者：
Guo Z;Chen Y;Mao YF;Zheng T;Jiang Y;Yan Y;Yin X;Zhang B
通讯作者：
Zhang B
影响因子：
3.5
作者：
Dubbelhuis, PF;Meijer, AJ
通讯作者：
Meijer, AJ
影响因子：
--
作者：
Gao, ZG;Zhang, XY;Ye, JP
通讯作者：
Ye, JP
影响因子：
3.1
作者：
Ahmed, Sara;Mahmood, Zahra;Zahid, Saadia
通讯作者：
Zahid, Saadia