Brain pericyte contractility, cerebral blood flow and blood-brain barrier integrity are impaired by normal aging and Alzheimer's disease amyloid-beta and are dependent on p75NTR

项目摘要/摘要 神经血管功能障碍与阿尔茨海默病(AD)的进展有关，在实验、成像、 病理学和流行病学研究。这些重要的发现导致了一种新兴的“神经血管” AD的假说，认为脑血管功能障碍在AD的发生和发展中起作用。 认知能力下降。越来越多的人认识到并有强有力的证据表明，神经血管解偶联，大脑 血流量(CBF)减少和调节失调，以及血脑屏障(BBB)的破坏，包括 周细胞的丢失是AD病理生理学级联反应的早期事件。周细胞是一种壁状细胞 毛细血管对维持血脑屏障至关重要，最近被牵连到监管中 CBF。重要的是，在AD中，周细胞恶化，血脑屏障降解。根据我们的初步调查结果，我们 假设周细胞是收缩细胞，调节毛细血管直径，从而调节CBF和BBB 在正常老化和Aβ40和Aβ42存在的情况下，这种周细胞调节功能受到损害。 P75NTR通路。为了验证这一假设，我将使用尖端方法，包括体内两种- 光子/共聚焦脑血管成像评估周细胞收缩、毛细血管直径、脑血流量变化和 BBB诚信。还将进行脑组织分析。我将确定脑周细胞是否保持收缩能力， 适当调节脑血流量，并在正常衰老和Aβ40和Aβ42(AIM)存在的情况下保持血脑屏障完整性 1/K99)。此外，我将确定正常衰老和Aβ40和Aβ42是否通过p75NTR损害大脑血脑屏障的完整性(目标2/ R00)。了解周细胞如何调节正常衰老和AD患者的CBF和BBB完整性 P75NTR的参与及其作为AD治疗靶点的潜力是及时和重要的。这是K99/R00 格兰特对我成功成为一名有影响力的终身教职助理教授至关重要，因为它 为我提供一项基本技术方面的培训，以研究未来的神经血管动力学 学习，并将提供专业培训，以提高口头报告和赠款写作 技能。

PROJECT SUMMARY/ ABSTRACT Neurovascular dysfunction has been linked to Alzheimer’s disease (AD) evolution in experimental, imaging, pathological, and epidemiological studies. These key findings have led to an emerging ‘neurovascular hypothesis’ of AD, which holds that cerebrovascular dysfunction contributes to the onset and progression of cognitive decline. There is growing appreciation and strong evidence that neurovascular uncoupling, cerebral blood flow (CBF) reductions and dysregulation, and breakdown of the blood-brain barrier (BBB), including the loss of pericytes, are early events in the AD pathophysiological cascade. Pericytes are mural cells on capillaries that are critical for the maintenance of the BBB, and have recently been implicated in the regulation of CBF. Importantly, pericytes deteriorate and the BBB degrades in AD. Based on our preliminary findings we hypothesize that pericytes are contractile cells that regulate capillary diameter and thereby CBF, and BBB integrity, and that this pericyte regulation is impaired in normal aging and in the presence of Aβ40 and Aβ42 via p75NTR pathway. To test this hypothesis, I will use cutting-edge approaches including in vivo two- photon/confocal brain vascular imaging to assess pericyte contractility, capillary diameter, CBF changes and BBB integrity. Brain tissue analysis will also be performed. I will determine if brain pericytes retain contractility, properly regulate CBF, and maintain BBB integrity in normal aging and in the presence of Aβ40 and Aβ42 (AIM 1/ K99). Also, I will determine if normal aging and Aβ40 and Aβ42 impair brain BBB integrity via p75NTR (AIM 2/ R00). Understanding how pericytes regulate CBF and BBB integrity in normal aging and AD and the involvement and potential of p75NTR as a therapeutic target for AD is timely and important. This K99/R00 grant is essential for my success in becoming an impactful tenure-track assistant professor because it provides me training in an essential technique to investigate neurovascular dynamics for future studies, and also will provide professional training in improving oral presentation and grant writing skills.