Neural activity dependent regulation of vascular: implications for Alzheimers disease

神经活动依赖性血管调节：对阿尔茨海默病的影响

• 批准号: 10641532
• 负责人: Richard Daneman
• 金额: $ 11.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641532
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Astrocytes; Biophysics; Blood; Blood Vessels; Blood flow; Brain; Cardiovascular Diseases; Cells; Cellular Membrane; Cellular Structures; Cerebral Amyloid Angiopathy; Cholesterol; Cholesterol Homeostasis; Clinical; Cognitive deficits; Cytoskeleton; Data; Endothelial Cells; Epidemiology; Functional disorder; Goals; Impaired cognition; Link; Mediating; Mediator; Microglia; Neurons; Nutrient; Oxygen; Process; Regulation; Role; Synapses; Testing; Therapeutic; brain endothelial cell; experimental study; mouse model; nervous system disorder; neural; neurovascular coupling; novel; prevent; therapeutic target; uptake

ABSTRACT Neurons rely on a continuous supply of oxygen and nutrients from the blood in order to function properly. To meet this need, local blood flow increases immediately following neural activity, a phenomenon known as neurovascular coupling (NVC). NVC involves is mediated by cellular interactions among neurons, astrocytes, mural cells, and endothelial cells (ECs). While NVC has been studied for over a century, there is still much unknown about this complicated process. A more active role for ECs in NVC has recently come to light, and there is likely much more to uncover regarding EC contribution to NVC. As NVC is crucial for proper brain function, NVC dysfunction can lead to cognitive deficits. NVC declines in aging and neurological diseases, with neural activity eliciting a weaker increase in blood flow. However, the mechanisms underlying NVC dysfunction are unclear. Our preliminary data show that neural activity dynamically regulates EC cholesterol synthesis and uptake. We also found that microglial depletion similarly alters EC cholesterol metabolism. As cellular membrane cholesterol content alters the rigidity and cytoskeletal structure of the cell, it may be that dynamic changes in EC cholesterol metabolism allow ECs to biophysically accommodate NVC. Interestingly, disruptions in cholesterol homeostasis are a strong risk factor for AD. We hypothesize that NVC leads to dynamic, activity-dependent changes in EC cholesterol metabolism, with microglia acting as mediators between synapses and ECs. We further hypothesize that EC cholesterol dysregulation occurs with NVC deficits in AD. In this proposal, we will first test the mechanistic link between NVC and EC cholesterol homeostasis. We will then investigate how microglia interact with neural activity in regulating EC cholesterol. Finally, we will assess neural activity-dependent regulation of EC cholesterol dynamics in a mouse model of AD with cerebral amyloid angiopathy. Together, the proposed experiments will advance our mechanistic understanding of the novel finding that neural activity regulates EC cholesterol metabolism. Furthermore, these data will identify whether therapeutic regulation of cholesterol synthesis or efflux specifically in brain ECs could be a successful clinical strategy for preventing NVC deficits in aging and AD.

摘要 神经元依赖于来自血液的氧气和营养物质的持续供应，以便正常工作。到 为了满足这种需要，神经活动后局部血流立即增加，这种现象称为 神经血管偶联（NVC）。NVC涉及由神经元、星形胶质细胞， 壁细胞和内皮细胞（EC）。虽然NVC已经被研究了世纪，但仍然有很多 对这个复杂的过程一无所知。EC在NVC中的一个更积极的角色最近已经曝光， 关于EC对NVC的贡献，可能还有更多的东西要发现。 由于NVC对正常的大脑功能至关重要，NVC功能障碍可能导致认知缺陷。NVC下降， 衰老和神经系统疾病，神经活动引起的血流量增加较弱。但 NVC功能障碍的潜在机制尚不清楚。我们的初步数据显示， 调节EC胆固醇的合成和摄取。我们还发现，小胶质细胞耗竭同样改变EC 胆固醇代谢由于细胞膜胆固醇含量改变了刚性和细胞骨架结构， 细胞，这可能是EC胆固醇代谢的动态变化允许EC生物调节 NVC。有趣的是，胆固醇稳态的破坏是AD的一个强有力的危险因素。我们假设 NVC导致EC胆固醇代谢的动态、活性依赖性变化，小胶质细胞充当 突触和EC之间的介质。我们进一步假设EC胆固醇失调发生在 AD中的NVC缺陷。在这个建议中，我们将首先测试NVC和EC胆固醇之间的机械联系 体内平衡然后，我们将研究小胶质细胞如何与神经活动相互作用，调节EC胆固醇。 最后，我们将评估AD小鼠模型中EC胆固醇动力学的神经活性依赖性调节 大脑淀粉样血管病总之，拟议的实验将推进我们的机械 了解神经活动调节EC胆固醇代谢的新发现。而且这些 数据将确定是否治疗调节胆固醇合成或流出，特别是在脑内皮细胞， 是一个成功的临床策略，预防NVC赤字老化和AD。