Amelioration of Hippocampal Insulin Resistance Reduces Tau Hyperphosphorylation and Cognitive Decline Induced by Isoflurane in Mice.
Amelioration of Hippocampal Insulin Resistance Reduces Tau Hyperphosphorylation and Cognitive Decline Induced by Isoflurane in Mice.
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改善海马胰岛素抵抗可减少小鼠 Tau 蛋白过度磷酸化和异氟烷引起的认知下降
DOI：
10.3389/fnagi.2021.686506
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发表时间：
2021
影响因子：
4.8
通讯作者：
Gu X
中科院分区：
文献类型：
--
作者：
Peng L;Fang X;Xu F;Liu S;Qian Y;Gong X;Zhao X;Ma Z;Xia T;Gu X
全身麻醉药会导致认知障碍，增加阿尔茨海默病(AD)的风险。然而，潜在的机制仍不清楚。我们先前的研究表明，长期异氟醚暴露可诱导成年小鼠的外周和中枢胰岛素抵抗(IR)，并加重2型糖尿病(T2 DM)小鼠的IR。临床和临床前研究表明，在AD和其他tau病中，胰岛素信号转导受损与tau病理之间存在关联。我们研究了抗糖尿病药物二甲双胍是否可以减轻tau蛋白过度磷酸化和异氟醚引起的小鼠认知功能减退。在成年野生型(WT)小鼠和高脂饮食加链脲佐菌素(HFD/STZ)2型糖尿病小鼠模型上，观察了长时间(6h)异氟醚麻醉对小鼠海马IR、tau蛋白过度磷酸化和海马依赖的认知功能的影响。在这里，我们显示了异氟醚和HFD/STZ显著和协同地诱导了海马区IR和恐惧记忆障碍。二甲双胍可显著改善异氟醚所致WT小鼠的海马区IR和认知功能障碍，但对T2 DM小鼠效果较差。异氟醚也诱导了海马tau的过度磷酸化，二甲双胍逆转了这一作用。此外，异氟醚显著提高成年和T2 DM小鼠的血糖水平，二甲双胍也逆转了这一作用。给二甲双胍预处理的小鼠注射25%的葡萄糖可诱导高血糖，但令人惊讶的是，在异氟醚麻醉后，二甲双胍对海马胰岛素信号和恐惧记忆的益处并未逆转。我们的研究结果表明，海马区IR和tau蛋白过度磷酸化与异氟醚诱导的急性认知功能障碍有关。短暂的二甲双胍治疗可以通过一种独立于血糖控制的机制来缓解这些影响。需要进一步研究长期应用二甲双胍是否也能预防T2 DM诱导的海马区IR和认知功能减退。
General anesthetics can induce cognitive impairments and increase the risk of Alzheimer’s disease (AD). However, the underlying mechanisms are still unknown. Our previous studies shown that long-term isoflurane exposure induced peripheral and central insulin resistance (IR) in adult mice and aggravated IR in type 2 diabetes mellitus (T2DM) mice. Clinical and preclinical studies revealed an association between impaired insulin signaling and tau pathology in AD and other tauopathies. We investigated if alleviation of hippocampal IR by the antidiabetic agent metformin could reduce tau hyperphosphorylation and cognitive decline induced by isoflurane in mice. The effects of prolonged (6 h) isoflurane anesthesia on hippocampal IR, hippocampal tau hyperphosphorylation, and hippocampus-dependent cognitive function were evaluated in wild type (WT) adult mice and the high-fat diet plus streptozotocin (HFD/STZ) mouse model of T2DM. Here we shown that isoflurane and HFD/STZ dramatically and synergistically induced hippocampal IR and fear memory impairment. Metformin pretreatment strongly ameliorated hippocampal IR and cognitive dysfunction caused by isoflurane in WT mice, but was less effective in T2DM mice. Isoflurane also induced hippocampal tau hyperphosphorylation and metformin reversed this effect. In addition, isoflurane significantly increased blood glucose levels in both adult and T2DM mice, and metformin reversed this effect as well. Administration of 25% glucose to metformin-pretreated mice induced hyperglycemia, but surprisingly did not reverse the benefits of metformin on hippocampal insulin signaling and fear memory following isoflurane anesthesia. Our findings show hippocampal IR and tau hyperphosphorylation contribute to acute isoflurane-induced cognitive dysfunction. Brief metformin treatment can mitigate these effects through a mechanism independent of glycemic control. Future studies are needed to investigate whether long-term metformin treatment can also prevent T2DM-induced hippocampal IR and cognitive decline.
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影响因子：
4.8
作者：
He, Xi;Long, Ge;Ouyang, Wen
通讯作者：
Ouyang, Wen
影响因子：
3.7
作者：
Jose Ramos-Rodriguez, Juan;Ortiz, Oscar;Garcia-Alloza, Monica
通讯作者：
Garcia-Alloza, Monica
影响因子：
8
作者：
Feinkohl, I.;Winterer, G.;Pischon, T.
通讯作者：
Pischon, T.
影响因子：
5.1
作者：
Cho, N. H.;Shaw, J. E.;Malanda, B.
通讯作者：
Malanda, B.
影响因子：
120.7
作者：
Menke, Andy;Casagrande, Sarah;Cowie, Catherine C.
通讯作者：
Cowie, Catherine C.