Mechanisms underlying sporadic Alzheimer's disease

散发性阿尔茨海默病的潜在机制

• 批准号: 10412101
• 负责人: Orly Lazarov
• 金额: $ 59.12万
• 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: 2018-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412101
• 关键词: 3-Dimensional; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein Precursor; Attenuated; Binding Proteins; Blood - brain barrier anatomy; Blood Vessels; Brain; Caveolins; Chronic; Cognitive deficits; Deterioration; Development; Diabetes Mellitus; Diabetic mouse; Disease; Endothelial Cells; Endothelium; Epidermal Growth Factor; Exhibits; Fibroblast Growth Factor; Growth Factor; Growth Factor Receptors; Hippocampus (Brain); Image; Impaired cognition; Impairment; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Knock-in; Knock-out; Learning; Membrane; Memory; Metabolism; Molecular; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Play; Risk; Role; Scaffolding Protein; Testing; Therapeutic; Transgenic Mice; Up-Regulation; amyloid precursor protein processing; base; brain endothelial cell; caveolin 1; cytokine; db/db mouse; experimental study; insulin signaling; mouse model; nerve stem cell; neurogenesis; neuropathology; novel; protein expression; protein metabolism; receptor expression; receptor upregulation; reconstitution; reconstruction; systemic inflammatory response; two-photon; uptake

ABSTRACT More than 95% of the Alzheimer’s patients have the sporadic disease. The mechanisms by which sporadic Alzheimer’s disease (AD) develops are not fully understood. Type 2 diabetes mellitus (T2DM) increases the risk of developing AD, suggesting a common mechanism induced by T2DM, leading to AD. Here we show that the expression of the endothelial protein caveolin-1 (Cav-1) is reduced in the MKR diabetic mouse model. Cav-1 expression is progressively lost in endothelial cells as a function of disease deterioration. We provide evidence that loss of Cav-1 is due to increased pro- inflammatory cytokines in the MKR mice. We further show that loss of endothelial Cav- 1 compromises the expression of insulin receptor and the transport of insulin into the brain. In addition, loss of Cav-1 results in reduced hippocampal neurogenesis, impairments in critical neurogenic receptors and upregulation of amyloid precursor protein (APP) in the hippocampus. These alterations are manifested by impaired learning and memory in MKR diabetic mice. This study will test the hypothesis that chronic inflammation associated with T2DM causes progressive endothelial Cav-1 depletion ultimately leading to AD. Aim 1 will determine the effect of Cav-1 depletion on insulin transport and uptake in T2DM mouse models, endothelial-specific conditional Cav-1-/- (Cdh5-CreERT2/Cav-1loxlox) and Cav-1-reconstituted MKR (EC-Cav1- RC/MKR) transgenic mice. Aim 2 will determine the effect of Cav-1 depletion on hippocampal plasticity and neurogenesis in T2DM mouse models. Aim 3 will examine the effect of Cav-1 depletion on APP metabolism, the development of neuropathology and impaired learning and memory in T2DM. Experiments will examine whether reconstitution of Cav-1 in endothelial cells of diabetic mice (EC-Cav1-RC/MKR) will rescue cognitive deficits and attenuate neuropathology. This study will establish a novel mechanism underlying sporadic AD and determine the therapeutic value of intervention in Cav-1 metabolism.

摘要 95%以上的阿尔茨海默病患者为散发性疾病。的机制 散发性阿尔茨海默病（AD）的发病机制尚不完全清楚。2型 糖尿病（T2 DM）增加了AD的风险，这表明 T2 DM导致AD的机制。在这里，我们表明，表达式的 在MKR糖尿病小鼠模型中，内皮蛋白小窝蛋白-1（Cav-1）减少。 Cav-1表达在内皮细胞中作为疾病的函数逐渐丧失 恶化我们提供的证据表明，Cav-1的损失是由于增加的亲， MKR小鼠中的炎性细胞因子。我们进一步表明，内皮细胞Cav- 1损害了胰岛素受体的表达和胰岛素转运到 个脑袋此外，Cav-1的缺失导致海马神经发生减少， 关键神经源性受体的损伤和淀粉样蛋白前体的上调 蛋白质（APP）在海马。这些变化表现为 MKR糖尿病小鼠的学习和记忆。本研究将检验以下假设： 与T2 DM相关的慢性炎症导致进行性内皮Cav-1 最终导致AD。目的1将确定Cav-1耗竭的效果 对T2 DM小鼠模型中胰岛素转运和摄取的影响，内皮特异性 条件Cav-1-/-（Cdh 5-CreERT 2/Cav-1 loxlox）和Cav-1-重建的MKR（EC-Cav 1- RC/MKR）转基因小鼠。目的2将确定Cav-1耗尽对细胞增殖的影响。 2型糖尿病小鼠模型海马可塑性和神经发生。目标3将检查 Cav-1缺失对APP代谢的影响，神经病理学的发展， 以及2型糖尿病患者的学习和记忆受损。实验将检验 Cav-1在糖尿病小鼠内皮细胞中的重建（EC-Cav 1-RC/MKR）将 挽救认知缺陷和减轻神经病理学。这项研究将建立一部小说 散发性AD的潜在机制，并确定干预的治疗价值 在Cav-1代谢中。