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: 10086748
• 负责人: Orly Lazarov
• 金额: $ 15.36万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10086748
• 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

Project Summary / Abstract 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.

项目摘要 /摘要 这项研究的目的是检验以下假设，即可爱素-1的耗竭加速了阿尔茨海默氏症 衰老和衰老的合并症（例如2型糖尿病）中的表型。 Caveolin-1（Cav-1）是主要的 Caveolae的组成部分，是脂质筏的关键参与者。 CAV-1表达在衰老中降低。我们在这里显示 Cav-1表达在两个型糖尿病的两种鼠标模型的大脑中逐渐丢失 年龄和疾病恶化。 2型糖尿病是阿尔茨海默氏病（AD）的危险因素。我们提供 这些小鼠中Cav-1耗竭的证据导致（1）淀粉样蛋白水解诱导淀粉样蛋白 前体蛋白质（APP）（2）受损的脉管系统（3）受损的海马神经发生（4）受损 学习和记忆（5）损害了胰岛素进入大脑的运输，并下调了 胰岛素受体。这项研究将检验以下假设：大脑中小窝蛋白-1的耗竭会加速 诱导淀粉样变性和损害胰岛素供应的AD表型导致认知 障碍。使用T2DM小鼠模型和CAV-1转基因小鼠AIM 1将通过 哪种CAV-1部署会影响应用程序代谢，神经病理学的发展和学习受损 和这些小鼠的记忆。 AIM 2将确定CAV-1部署对胰岛素运输和摄取的影响。 AIM 3将确定CAV-1耗竭对脉管系统和海马神经发生的影响。 实验将检查糖尿病小鼠内皮细胞中CAV-1的重构是否会救出 认知缺陷并减弱神经病理学。这项研究将确定CAV-1在开发中的作用 AD并确定CAV-1代谢中干预的治疗价值。