Acceleration of AD Phenotypes in Asymptomatic Mouse Models

无症状小鼠模型中 AD 表型的加速

• 批准号: 10407994
• 负责人: Orly Lazarov
• 金额: $ 39.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407994
• 关键词: 3-Dimensional; Abeta synthesis; Acceleration; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein Precursor; Amyloidosis; Attenuated; Binding Proteins; Blood Vessels; Brain; Caveolae; Cell Culture Techniques; Cognitive; Cognitive deficits; Deterioration; Development; Diabetic mouse; Disease; Disease Progression; Down-Regulation; Endothelial Cells; Endothelium; Hippocampus (Brain); Image; Impaired cognition; Impairment; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Knock-in; Knock-out; Knockout Mice; Learning; Level of Evidence; Link; Membrane; Membrane Microdomains; Memory; Memory impairment; Metabolism; Modeling; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathologic; Pathway interactions; Phenotype; Proteolysis; Receptor Signaling; Role; Signal Transduction; Swedish mutation; Testing; Therapeutic; Transgenic Mice; amyloid precursor protein processing; amyloidogenesis; caveolin 1; comorbidity; db/db mouse; diabetic; disease phenotype; experimental study; familial Alzheimer disease; insulin signaling; mouse model; neurogenesis; neuropathology; protein expression; protein metabolism; protein transport; receptor expression; reconstitution; reconstruction; recruit; trafficking; two-photon; uptake

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.

这项研究的目的是验证Caveolin-1的缺失加速阿尔茨海默氏症的假设。 表型在衰老和与衰老相关的合并症，如2型糖尿病。Caveolin-1（Cav-1）是主要的 细胞膜小窝的组成部分，也是脂筏的重要组成部分。Cav-1的表达随着年龄的增长而减少。在此我们表明 Cav-1表达在2型糖尿病小鼠模型的大脑中逐渐丧失， 年龄和疾病的恶化。2型糖尿病是阿尔茨海默病（AD）的危险因素。我们提供 在这些小鼠中Cav-1的消耗导致（1）诱导淀粉样蛋白的淀粉样蛋白水解 前体蛋白（APP）（2）血管受损（3）海马神经发生受损（4）受损 学习和记忆（5）胰岛素进入大脑的运输受损， 胰岛素受体这项研究将测试大脑中Caveolin-1的消耗加速了大脑中的细胞凋亡的假设。 AD表型通过诱导淀粉样变性和损害胰岛素供应到大脑中，导致认知功能障碍， 损伤利用T2 DM小鼠模型和Cav-1转基因小鼠，Aim 1将通过 Cav-1缺失影响APP代谢、神经病理学的发展和学习障碍 和记忆的能力。目的2将确定Cav-1缺失对胰岛素转运和摄取的影响。 目的3将确定Cav-1缺失对血管和海马神经发生的影响。 实验将检查Cav-1在糖尿病小鼠的内皮细胞中的重建是否会拯救糖尿病小鼠的血管。 认知缺陷和减弱的神经病理学。这项研究将建立Cav-1在发展中的作用， 的AD，并确定干预Cav-1代谢的治疗价值。