Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
J Alzheimers Dis. 2023;95(3):1041-1058. doi: 10.3233/JAD-230392.
Several epidemiological data revealed an association between Alzheimer's disease (AD) and type 2 diabetes. Researchers concentrated on brain insulin resistance with little emphasis on the link between systemic insulin resistance and AD, despite the fact that the incidence of type 2 diabetes is higher in AD patients and that impairment in insulin signaling is a risk factor for AD.
The goal of this study is to determine the role of systemic insulin resistance in the pathogenesis of Alzheimer's disease by evaluating the consequences of tau loss-of-function on peripheral insulin sensitivity.
Primary hepatocytes isolated from transgenic mouse models (Tau KO, P301 L) and wild type mice (C57BL/6) were evaluated for their insulin sensitivity using glucose uptake assays as well as biochemical analysis of insulin signaling markers.
Our data show that tau deletion or loss of function promotes peripheral insulin resistance as seen in primary hepatocytes isolated from Tau KO and P301 L mice, respectively. Furthermore, exposure of wild-type primary hepatocytes to sub-toxic concentrations of tau oligomers results in a dose-dependent inhibition of glucose uptake, associated with downregulation of insulin signaling. Tau oligomers-induced inactivation of insulin signaling proteins was rescued by inhibition of p38 MAPK, suggesting the involvement of p38 MAPK.
This is the first study testing tau role in peripheral insulin resistance at the cellular level using multiple transgenic mouse models. Moreover, this study suggests that tau should be functional for insulin sensitivity, therefore, any loss of function by deletion or aggregation would result in insulin resistance.
多项流行病学数据显示阿尔茨海默病（AD）与 2 型糖尿病之间存在关联。研究人员主要关注大脑胰岛素抵抗，而对全身胰岛素抵抗与 AD 之间的联系关注较少，尽管 2 型糖尿病在 AD 患者中的发病率更高，且胰岛素信号受损是 AD 的一个风险因素。
本研究旨在通过评估 tau 功能丧失对周围胰岛素敏感性的影响，确定全身胰岛素抵抗在阿尔茨海默病发病机制中的作用。
使用葡萄糖摄取测定法以及胰岛素信号标志物的生化分析，评估来自转基因小鼠模型（Tau KO、P301L）和野生型小鼠（C57BL/6）的原代肝细胞的胰岛素敏感性。
我们的数据表明，tau 缺失或功能丧失分别促进了来自 Tau KO 和 P301L 小鼠的原代肝细胞中的外周胰岛素抵抗。此外，将野生型原代肝细胞暴露于低毒性浓度的 tau 寡聚物中，会导致葡萄糖摄取呈剂量依赖性抑制，同时伴随着胰岛素信号下调。tau 寡聚物诱导的胰岛素信号蛋白失活可通过抑制 p38 MAPK 得到挽救，这表明 p38 MAPK 的参与。
这是首次使用多种转基因小鼠模型在细胞水平上测试 tau 在周围胰岛素抵抗中的作用的研究。此外，本研究表明 tau 对于胰岛素敏感性是必需的，因此，任何缺失或聚集导致的功能丧失都会导致胰岛素抵抗。
