Mechanisms underlying sporadic Alzheimer's disease

散发性阿尔茨海默病的潜在机制

• 批准号: 9756289
• 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: 2018-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756289
• 关键词: 3-Dimensional; Alzheimer' s Disease; 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; Patients; 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; 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 超过95%的阿尔茨海默氏症患者患有散发性疾病。其作用机制 散发性阿尔茨海默病(AD)的发病机制尚不完全清楚。类型2 糖尿病(T2 DM)增加了患AD的风险，这表明 T2 DM诱发AD的机制。在这里，我们展示了 内皮蛋白小窝蛋白-1(Cav-1)在MKR糖尿病小鼠模型中减少。 作为疾病的一种功能，Cav-1在血管内皮细胞中的表达逐渐丧失 恶化。我们提供的证据表明，CAV-1的损失是由于PRO增加所致 MKR小鼠体内的炎性细胞因子。我们进一步表明，内皮细胞腔静脉的丧失- 1影响胰岛素受体的表达和胰岛素向血管内的转运 大脑。此外，Cav-1的缺失会导致海马神经发生减少， 关键神经源性受体的损伤与淀粉样前体的上调 海马体中的蛋白质(APP)。这些改变表现为损害 MKR糖尿病小鼠的学习和记忆。这项研究将检验这一假设 与T2 DM相关的慢性炎症导致进行性内皮细胞Cav-1 消耗最终导致AD。目标1将确定Cav-1耗竭的影响 内皮特异型T2 DM小鼠模型对胰岛素转运和摄取的影响 条件性Cav-1-/-(CDH5-CreerT2/Cav-1loxlox)和Cav-1-重组MKR(EC-Cav1- RC/MKR)转基因小鼠。目标2将确定Cav-1耗竭对 T2 DM小鼠模型的海马区可塑性和神经发生。Aim 3将审查 Cav-1缺失对APP代谢及神经病理学发展的影响 T2 DM患者的学习记忆功能受损。实验将检验 重组Cav-1在糖尿病小鼠内皮细胞(EC-Cav1-RC/MKR)中的作用 挽救认知缺陷，减轻神经病理。这项研究将建立一部小说 散发性阿尔茨海默病的发病机制及干预治疗价值的确定 在Cav-1新陈代谢中。