Investigation of cerebrovascular Notch as a novel modulator of cognitive function

脑血管Notch作为认知功能新型调节剂的研究

• 批准号: 10570279
• 负责人: Stephanie Renee Niemczyk
• 金额: $ 9.8万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10570279
• 关键词: Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Animal Model; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Pathology; Cardiovascular system; Cell Adhesion Molecules; Cells; Cerebrovascular Disorders; Cerebrovascular system; Cognition; Development; Diabetes Mellitus; Disease; Disease Progression; Endothelium; Environment; Epidemic; Etiology; Functional disorder; Genetic; Goals; Hippocampus; Impaired cognition; Impairment; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Intervention; Investigation; Label; Late Onset Alzheimer Disease; Learning; Ligands; Link; Long-Term Effects; Maintenance; Mediating; Memory; Metabolic; Metabolic Diseases; Morphology; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Pore Complex; Obesity; Pathogenesis; Pathogenicity; Pathologic; Penetrance; Peripheral; Persons; Play; Population; Population Study; Process; Proliferating; Public Health; Regulation; Risk; Role; Signal Pathway; Signal Transduction; Study models; Testing; Time; Tracer; United States; aging population; angiogenesis; blood-brain barrier penetration; brain endothelial cell; cardiovascular risk factor; cell type; cerebrovascular; chemokine; cognitive function; cytokine; density; diet-induced obesity; familial Alzheimer disease; immune activation; immune cell infiltrate; insight; modifiable risk; mouse model; neurogenesis; neuroinflammation; notch protein; novel; obesity development; preservation; response; single-cell RNA sequencing; therapeutic target; therapeutically effective; vascular inflammation

Project Summary Alzheimer’s disease (AD) afflicts over 6 million people in the United States, and this number is expected to climb to nearly 13 million by 2050. The development of effective therapeutics is hampered not only by an incomplete understanding of the pathogenic cascades underlying AD development, but the challenges of identifying disease-modifying therapies that are also capable of blood-brain barrier penetrance. Increasing evidence implicates cerebrovascular dysfunction in the pathogenesis of AD, and cardiovascular risk factors such as obesity and diabetes increase the risk of late-onset AD up to two-fold. Brain microvascular endothelial cells (BMEC) act simultaneously as a barrier and interface between the central and peripheral environment and contribute to the regulation of processes such as neurogenesis and neuroinflammation via expression of angiocrine signaling factors. Dysregulation of neurogenesis and neuroinflammation are associated with AD pathology as well as obesity and diabetes. Notch proteins are part of an evolutionarily conserved signaling axis and play critical roles in the development and maintenance of vascular function. In the brain, dysregulation of endothelial Notch (EC-Notch) signaling leads to dysregulation of neurogenesis and blood-brain barrier integrity. Our preliminary studies have found that Notch signaling in the brain endothelium changes with age, is disrupted in AD, and inhibition of EC-Notch signaling is protective against AD-induced cognitive impairment. Although Notch is a well-described regulator of angiogenesis, we did not find overt changes in vascular morphology or density in response to Notch inhibition, suggesting that preservation of cognitive function may result from altered angiocrine signaling to neural cells. Alterations in Notch signaling are observed in response to, and modulate the course of, diet-induced obesity (DIO). Thus, dysregulation of EC-Notch signaling in response to DIO may present a mechanistic link between cardiovascular risk factors and AD pathology. This study will test the hypothesis that EC-Notch signaling contributes to the dysregulation of neuroinflammation and neurogenesis during AD and DIO-induced cognitive impairment. Using inducible genetic inhibition of EC-Notch, we will investigate its role in regulating adult hippocampal neurogenesis and neuroinflammation in a mouse model of AD, with the goal of identifying angiocrine signaling factors which mediate these effects. Because Notch signaling is influenced by, and capable of influencing, metabolic parameters such as obesity and insulin resistance, we will expand our studies to interrogate the role of EC-Notch in mediating cognitive impairment in response to DIO and insulin resistance. These studies will explore EC-Notch as a novel, common mechanism of cognitive decline in familial and late-onset AD and interrogate EC-Notch as a therapeutic target which does not require BBB penetration to exert influence on AD progression.

项目摘要 在美国，阿尔茨海默氏病（AD）遭受了600万人的困扰，这一数字是 预计到2050年将攀升至近1300万。有效疗法的发展不仅受到阻碍 通过对广告开发潜在的病原级联的不完全理解，但挑战 鉴定调解疾病的疗法，这些疗法也具有血脑屏障的渗透率。增加 证据暗示AD发病机理中的脑血管功能障碍，以及心血管危险因素此类脑血管功能障碍。 随着肥胖症和糖尿病的延迟广告的风险高达两倍。脑微血管内皮细胞 （BMEC）同时作为中央环境和外围环境之间的障碍和接口 通过表达神经发生和神经炎症等过程的调节 血管分泌信号传导因素。神经发生和神经炎症的失调与AD有关 病理以及肥胖和糖尿病。 Notch蛋白是进化配置的信号轴的一部分，并在 血管功能的开发和维护。在大脑中，内皮缺陷的失调（EC-NOTCH） 信号传导导致神经发生和血脑屏障完整性的失调。我们的初步研究 发现脑内皮中的Notch信号随着年龄的年龄而变化，在AD中受到破坏，并抑制 EC-NOTCH信号受到保护，免受AD诱导的认知障碍。虽然Notch是一个很好的描述 血管生成的调节剂，我们没有发现响应缺口的血管形态或密度的明显变化 抑制作用，表明保留认知功能可能是由于血管分泌信号变化对中性的 细胞。响应于饮食诱导的响应并调节Notch信号的改变 肥胖（Dio）。那就是响应DIO的EC-NOTCH信号的失调可能会呈现机械链接 在心血管危险因素和AD病理学之间。 这项研究将检验以下假设： AD和DIO诱导的认知障碍期间的神经炎症和神经发生。使用诱导 遗传抑制EC-NOTCH，我们将研究其在调节成人海马神经发生和 AD小鼠模型中的神经炎症，目的是识别血管分泌信号传导因子 调解这些效果。因为缺口信号受到影响和能力的影响，代谢 肥胖和胰岛素抵抗等参数，我们将扩展我们的研究以询问Ec-Notch的作用 在响应DIO和胰岛素抵抗时介导认知障碍。这些研究将探索Ec-Notch 作为一种新颖的家庭认知下降的常见机制和迟到的广告，并质疑ec-notch 不需要BBB渗透来对AD进展产生影响的治疗靶标。