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 神经元依赖于血液中的氧气和营养素的连续供应，以便正常运行。到 满足这种需求，神经活动后立即增加局部血流，这种现象称为 神经血管耦合（NVC）。 NVC涉及的是由神经元，星形胶质细胞之间的细胞相互作用介导的 壁细胞和内皮细胞（EC）。尽管NVC已被研究了一个多世纪，但仍然有很多 关于这个复杂的过程未知。 EC在NVC中的更为积极作用最近已经曝光，并且 关于EC对NVC的贡献，可能还有更多要揭示的。 由于NVC对于适当的大脑功能至关重要，因此NVC功能障碍会导致认知缺陷。 NVC下降 衰老和神经系统疾病，神经活动会引起血流较弱的增加。但是， NVC功能障碍的基础机制尚不清楚。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，小胶质耗尽类似地改变了EC 胆固醇代谢。随着细胞膜胆固醇的含量改变了刚性和细胞骨架结构 细胞，可能是EC胆固醇代谢的动态变化使EC可以生物物理适应 NVC。有趣的是，胆固醇稳态的干扰是广告的强大危险因素。我们假设这一点 NVC导致EC胆固醇代谢的动态，活动依赖性变化，而小胶质细胞的作用为 突触与EC之间的介体。我们进一步假设EC胆固醇失调发生在 AD中的NVC缺陷。在此提案中，我们将首先测试NVC和EC胆固醇之间的机械联系 稳态。然后，我们将研究小胶质细胞在调节EC胆固醇时如何与神经活性相互作用。 最后，我们将评估AD小鼠模型中EC胆固醇动力学的神经活动依赖性调节 脑淀粉样血管病。提出的实验将共同提高我们的机械 了解神经活动调节EC胆固醇代谢的新颖发现。此外，这些 数据将确定胆固醇合成的治疗调节还是专门在脑EC中进行的。 成为预防NVC衰老和AD中NVC缺陷的成功临床策略。