Neural activity dependent regulation of vascular: implications for Alzheimers disease

摘要 神经元依靠血液中持续的氧气和营养物质才能正常运作。至 为了满足这种需求，局部血流量在神经活动后立即增加，这种现象被称为 神经血管偶联(NVC)。NVC的参与是通过神经元、星形胶质细胞、 壁细胞和内皮细胞(ECs)。虽然NVC已经被研究了一个多世纪，但仍然有很多 对这个复杂的过程一无所知。欧洲经济共同体在NVC中扮演的更积极的角色最近浮出水面，以及 关于欧共体对NVC的贡献，可能会有更多的发现。 由于NVC对正常的大脑功能至关重要，NVC功能障碍可能会导致认知障碍。NVC在 衰老和神经疾病，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。我们的初步数据显示，神经活动动态地 调节EC胆固醇的合成和摄取。我们还发现，小胶质细胞的枯竭同样会改变EC 胆固醇代谢。由于细胞膜胆固醇含量改变了细胞的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允许ECs在生物物理上适应 NVC。有趣的是，胆固醇动态平衡的破坏是AD的一个重要风险因素。我们假设 NVC导致EC胆固醇代谢的动态、活性依赖的变化，小胶质细胞起作用 突触和内皮细胞之间的介体。我们进一步假设，EC胆固醇失调发生在 AD的NVC缺乏症。在这项提案中，我们将首先测试NVC和EC胆固醇之间的机制联系 动态平衡。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性依赖性调节 患有脑淀粉样血管病。总之，拟议中的实验将推动我们的机械化 对神经活动调节EC胆固醇代谢这一新发现的理解。此外，这些 数据将确定特定于脑内皮细胞的胆固醇合成或外流的治疗性调节是否可以 是预防衰老和AD中NVC缺陷的一种成功的临床策略。

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.