Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer’s disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer’s disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications.

中文翻译：

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Tau过度磷酸化诱导神经元中的低聚胰岛素蓄积和胰岛素抵抗

胰岛素信号传导缺陷和胰岛素抵抗已直接与神经退行性疾病（如阿尔茨海默氏病）的进展相关。然而，迄今为止，对于病理条件下的潜在分子机制或胰岛素在脑中的状态和分布知之甚少。在这里，我们报道了在阿尔茨海默氏病和几种最普遍的人类tauopathies中，高磷酸化的tau蛋白携带的神经元中胰岛素以寡聚体的形式积累和保留。胰岛素在神经元内的积累直接取决于tau过度磷酸化，并跟随tauopathy的进展。此外，积聚胰岛素的细胞显示出胰岛素抵抗的迹象，胰岛素受体水平降低。