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Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice

机译：二甲双胍可减轻肥胖的瘦素抵抗小鼠的阿尔茨海默氏病样神经病理

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Diabetes increases the risk of Alzheimer's disease (AD). The pathological hallmarks for AD brains are extracellular amyloid plaques formed by β-amyloid peptide (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. This study was designed to determine AD-like brain changes in mice modeling for type 2 diabetes. The effects of metformin on these changes also were studied. Seven-week old male db/db mice received intraperitoneal injection of 200 mg kg - 1 d - 1 metformin for 18 weeks. They were subjected to Barnes maze at an age of 21 weeks and fear conditioning at an age of 24 weeks to assess their cognitive functions. Hippocampus was harvested after these tests for biochemical evaluation. The db/db mice had more tau phosphorylated at S396 and total tau in their hippocampi than their non-diabetic control db + mice. Activated/phosphorylated c-jun N-terminal kinase (JNK), a tau kinase, was increased in the db/db mouse hippocampus. Metformin attenuated the increase of total tau, phospho-tau and activated JNK. The db/db mice had increased Aβ levels. Metformin attenuated the reduction of synaptophysin, a synaptic protein, in the db/db mouse hippocampus. Metformin did not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia in the db/db mice. Our results suggest that the db/db mice have multiple AD-like brain changes including impaired cognitive functions, increased phospho-tau and Aβ as well as decreased synaptic proteins. Activation of JNK may contribute to the increased phospho-tau in the db/db mice. Metformin attenuates AD-like biochemical changes in the brain of these mice.
机译：糖尿病会增加阿尔茨海默氏病（AD）的风险。 AD脑的病理标志是由β淀粉样肽（Aβ）和由磷酸化tau蛋白组成的细胞内神经原纤维缠结形成的细胞外淀粉样斑块。这项研究旨在确定2型糖尿病小鼠的AD样大脑变化。还研究了二甲双胍对这些变化的影响。七周大的雄性db / db小鼠接受了200 mg kg-1 d-1二甲双胍的腹膜内注射，持续18周。他们在21周龄时经历了Barnes迷宫，在24周龄时经历了恐惧调节，以评估其认知功能。这些测试后收获海马用于生化评估。与非糖尿病对照db +小鼠相比，db / db小鼠的S396磷酸化tau蛋白和海马总tau蛋白含量更高。在db / db小鼠海马中，活化/磷酸化的c-jun N末端激酶（JNK）（一种tau激酶）增加。二甲双胍减弱总tau，磷酸化tau和活化JNK的增加。 db / db小鼠的Aβ水平升高。二甲双胍可减轻db / db小鼠海马突触素的减少。二甲双胍不会减轻db / db小鼠的空间学习和记忆障碍以及长期高血糖症。我们的研究结果表明，db / db小鼠具有多种AD样大脑变化，包括认知功能受损，磷酸化tau和Aβ升高以及突触蛋白降低。 JNK的激活可能导致db / db小鼠的磷酸化tau升高。二甲双胍减弱了这些小鼠大脑中类似AD的生化变化。

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