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.

抽象的 神经元依靠血液持续供应氧气和营养物质才能正常运作。到 满足这种需要，神经活动后局部血流量立即增加，这种现象称为 神经血管耦合（NVC）。 NVC 涉及由神经元、星形胶质细胞、 壁细胞和内皮细胞（EC）。尽管 NVC 的研究已经有一个多世纪了，但仍有很多问题需要解决。 不知道这个复杂的过程。最近，EC 在 NVC 中发挥了更积极的作用，并且 关于 EC 对 NVC 的贡献，可能还有更多的东西有待发现。 由于 NVC 对于正常的大脑功能至关重要，因此 NVC 功能障碍会导致认知缺陷。 NVC 下跌 衰老和神经系统疾病，神经活动引起的血流量增加较弱。然而， NVC 功能障碍的机制尚不清楚。我们的初步数据表明，神经活动动态 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会改变 EC 胆固醇代谢。由于细胞膜胆固醇含量改变了细胞膜的刚性和细胞骨架结构 对于细胞来说，EC 胆固醇代谢的动态变化可能使 EC 在生物物理上适应 雷士。有趣的是，胆固醇稳态的破坏是 AD 的一个重要危险因素。我们假设 NVC 导致 EC 胆固醇代谢发生动态的、活动依赖性的变化，其中小胶质细胞充当 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。在本提案中，我们将首先测试 NVC 和 EC 胆固醇之间的机制联系 体内平衡。然后我们将研究小胶质细胞如何与调节 EC 胆固醇的神经活动相互作用。 最后，我们将评估 AD 小鼠模型中 EC 胆固醇动态的神经活动依赖性调节 患有脑淀粉样血管病。总之，所提出的实验将推进我们的机制 了解神经活动调节 EC 胆固醇代谢的新发现。此外，这些 数据将确定大脑 EC 中胆固醇合成或流出的治疗调节是否可以 是预防衰老和 AD 中 NVC 缺陷的成功临床策略。