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 阿尔茨海默病（AD）折磨着美国超过600万人，这个数字是 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， 由于对AD发展背后的致病级联反应的不完全理解， 确定也能够渗透血脑屏障的疾病改善疗法。增加 有证据表明，脑血管功能障碍与AD的发病机制有关， 因为肥胖和糖尿病会使晚发性AD的风险增加两倍。脑微血管内皮细胞 （BMEC）同时作为中心和外围环境之间的屏障和界面， 有助于调节过程，如神经发生和神经炎症通过表达 血管分泌信号因子。神经发生失调和神经炎症与AD相关 病理学以及肥胖和糖尿病。 Notch蛋白是进化上保守的信号传导轴的一部分，并且在细胞内信号传导中起关键作用。 发展和维持血管功能。在大脑中，内皮Notch（EC-Notch）调节异常 信号传导导致神经发生和血脑屏障完整性的失调。我们的初步研究表明 发现脑内皮细胞中的Notch信号随着年龄的变化而变化，在AD中被破坏， EC-Notch信号传导对AD诱导的认知障碍具有保护作用。虽然Notch是一个被描述得很好的 作为血管生成的调节因子，我们没有发现Notch引起的血管形态或密度的明显变化 抑制，这表明认知功能的保留可能是由于改变了血管分泌信号传导到神经元， 细胞观察到Notch信号传导的改变响应于饮食诱导的细胞凋亡，并调节其过程。 肥胖（DIO）。因此，响应于DIO的EC-Notch信号传导的失调可能存在机械联系， 心血管危险因素和AD病理之间的联系。 本研究将检验EC-Notch信号转导有助于细胞凋亡的失调的假设。 AD和DIO诱导的认知障碍期间的神经炎症和神经发生。使用诱导型 EC-Notch的遗传抑制，我们将研究其在调节成年海马神经发生中的作用， 在AD小鼠模型中的神经炎症，目的是鉴定血管分泌信号因子， 调节这些影响。由于Notch信号传导受代谢的影响，并且能够影响代谢， 参数，如肥胖和胰岛素抵抗，我们将扩大我们的研究，询问EC-Notch的作用， 介导DIO和胰岛素抵抗引起的认知障碍。这些研究将探索EC-Notch 作为家族性和迟发性AD认知功能下降的一种新的常见机制， 不需要BBB穿透就能影响AD进展的治疗靶点。