Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden.
Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Spain.
Brain. 2017 Dec 1;140(12):3269-3285. doi: 10.1093/brain/awx256.
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.
胰岛素信号转导缺陷和胰岛素抵抗与阿尔茨海默病等神经退行性疾病的进展直接相关。然而，迄今为止，对于病理状态下大脑中潜在的分子机制或胰岛素状态和分布知之甚少。在这里，我们报告胰岛素在阿尔茨海默病和几种最常见的人类 tau 病中，以高磷酸化 tau 为载体的神经元中积累并保留为寡聚物。胰岛素在神经元内的积累直接依赖于 tau 的过度磷酸化，并随 tau 病的进展而发生。此外，积累胰岛素的细胞表现出胰岛素抵抗和胰岛素受体水平降低的迹象。这些结果表明，高磷酸化 tau 携带神经元中胰岛素的保留是 tau 病中观察到的胰岛素抵抗的一个原因，并描述了一个具有重要治疗意义的新的神经病理学概念。
