Acceleration of AD Phenotypes in Asymptomatic Mouse Models

这项研究的目的是验证Caveolin-1耗尽会加速阿尔茨海默氏症的假设 衰老的表型和与衰老相关的并发症，如2型糖尿病。Caveolin-1(Cav-1)是主要的 小窝的成分，在脂筏中起关键作用。CAV-1的表达随着年龄的增长而降低。我们在这里展示 在两种2型糖尿病小鼠模型中，Cav-1的表达作为一种功能逐渐丧失 年龄和疾病恶化。2型糖尿病是阿尔茨海默病(AD)的危险因素。我们提供 这些小鼠中Cav-1的缺失导致(1)诱导淀粉样蛋白的产生 前体蛋白(APP)(2)血管系统受损(3)海马神经发生受损(4)受损 学习和记忆(5)影响胰岛素向大脑的运输，下调胰岛素的表达 胰岛素受体。这项研究将检验大脑中Caveolin-1的枯竭会加速 通过诱导淀粉样变性和影响脑内胰岛素供应而导致AD表型，导致认知 减损。利用T2 DM小鼠模型和CAV-1转基因小鼠，Aim 1将通过 哪种Cav-1缺失会影响APP代谢、神经病理发展和学习障碍 以及这些小鼠的记忆。目的2确定Cav-1缺失对胰岛素转运和摄取的影响。 目的3确定Cav-1缺失对血管形成和海马神经发生的影响。 实验将检验在糖尿病小鼠内皮细胞中重建Cav-1是否会挽救 认知障碍和减轻神经病理。这项研究将确定Cav-1在发育中的作用。 并确定干预Cav-1代谢的治疗价值。

The aim of this study is to test the hypothesis that depletion of Caveolin-1 accelerates the Alzheimer’s phenotype in aging and aging-linked comorbidities, such as type 2 diabetes. Caveolin-1 (Cav-1) is the principal component of caveolae, and a critical player in lipid rafts. Cav-1 expression is reduced in aging. Here we show that Cav-1 expression is progressively lost in the brains of two mouse models of type 2 diabetes as a function of age and disease deterioration. Type 2 diabetes is a risk factor for Alzheimer’s disease (AD). We provide evidence that depletion of Cav-1 in these mice results in (1) induction of amyloidogenic proteolysis of amyloid precursor protein (APP) (2) compromised vasculature (3) impaired hippocampal neurogenesis (4) impaired learning and memory (5) compromised transport of insulin into the brain and downregulated expression of insulin receptor. This study will test the hypothesis that depletion of Caveolin-1 in the brain accelerates the AD phenotype by inducing amyloidosis and compromising insulin supply into the brain, leading to cognitive impairments. Using T2DM mouse models and Cav-1 transgenic mice Aim 1 will examine the mechanism by which Cav-1 depletion affects APP metabolism, the development of neuropathology and impaired learning and memory in these mice. Aim 2 will determine the effect of Cav-1 depletion on insulin transport and uptake. Aim 3 will determine the effect of Cav-1 depletion on vasculature and hippocampal neurogenesis. Experiments will examine whether reconstitution of Cav-1 in endothelial cells of diabetic mice will rescue cognitive deficits and attenuate neuropathology. This study will establish the role of Cav-1 in the development of AD and determine the therapeutic value of intervention in Cav-1 metabolism.