神经元老化和衰老密切相关的阿尔茨海默病（老年痴呆，AD）的发生发展有着紧密的联系，但其机制还不清楚。二型糖尿病和AD都随着衰老的发生逐渐增加，并且前者是后者一个风险因素。其中一个主要原因是胰岛素持续暴露引发的外周和中枢神经系统的胰岛素抵抗。我们利用首次在正常饲养小鼠中鉴定出的“自发性胰岛素抵抗”模型，发现外周胰岛素抵抗会引起神经元的胰岛素抵抗，并会直接导致神经元的老化。通过对葡萄糖代谢通路的分析，鉴定出己糖激酶2是其一个重要的作用靶点，并初步探讨了其分子机制。本项目中，基于前期大量工作基础，我们拟利用 “自发性胰岛素抵抗”小鼠，结合衰老小鼠、AD小鼠等疾病模型，通过分子、细胞、生化等研究手段，利用遗传和靶点药物操作，阐明胰岛素抵抗诱导神经元衰老的分子机制，及其在老年痴呆疾病中的作用，为神经元衰老相关疾病的临床诊治提供理论依据和潜在的治疗靶点。

Neuronal senescence is closely related with the pathogenesis of Alzheimer’s disease which is primarily induced by aging. But the underling mechanism is unclear. Type 2 diabetes (T2D) and Alzheimer's disease both increase with age and the former is a risk factor for the latter. The chronic insulin exposure induced peripheral serum hyperinsulinemia is also reflected in the cerebrospinal fluid (CSF), and that chronical exposure to elevated CSF insulin renders neurons insulin resistant. We were surprised to find spontaneous insulin resistance in normal lab colonies of C57BL/6J mice. Using this model, we found that chronical insulin exposure elevates CSF insulin renders neurons insulin resistant leading to neuronal senescence and neuronal cell cycle dysregulation. We identified hexokinase-2 may be an important target for insulin resistance induced neuronal senescence. Based on our previous unpublished data and our work on neuronal cell cycle regulation, by using spontaneous insulin resistance mouse model, AD mouse model, Aging mice model, as well as genetic and pharmaceutical applications, we plan to illustrate the mechanism underling the insulin resistance-induced neuronal senescence. And explore its implication in the pathogenesis of AD. The current study will benefit from prevent and cure of neuronal senescence related neuronal disease.