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

项目总结/摘要 神经血管功能障碍与阿尔茨海默病（AD）的实验、成像、 病理学和流行病学研究。这些关键发现导致了一种新兴的“神经血管” 该假说认为脑血管功能障碍有助于AD的发生和进展， 认知能力下降有越来越多的认识和强有力的证据表明，神经血管解偶联，脑 血流量（CBF）减少和失调，以及血脑屏障（BBB）的破坏，包括 周细胞的损失是AD病理生理级联中的早期事件。周细胞是一种壁细胞 毛细血管是维持血脑屏障的关键，最近被牵连在调节 CBF的。重要的是，在AD中周细胞退化并且BBB降解。根据我们的初步调查结果， 假设周细胞是调节毛细血管直径从而调节CBF和BBB收缩细胞 在正常衰老和Aβ40和Aβ42存在的情况下，这种周细胞调节通过以下途径受损： p75 NTR通路。为了验证这一假设，我将使用尖端的方法，包括在体内两个- 光子/共聚焦脑血管成像，以评估周细胞收缩力、毛细血管直径、CBF变化和 BBB完整性。还将进行脑组织分析。我将确定大脑周细胞是否保持收缩性， 在正常老化和Aβ40和Aβ42存在的情况下，适当调节CBF，并维持BBB的完整性（AIM 1/ K99）。此外，我将确定正常老化和Aβ40和Aβ42是否通过p75 NTR损害脑BBB完整性（AIM 2/ R00）。了解周细胞如何调节正常衰老和AD中的CBF和BBB完整性， p75 NTR作为AD治疗靶点的参与和潜力是及时和重要的。K99/R00 格兰特是我成功成为一个有影响力的终身助理教授，因为它 为我提供了一个基本的技术培训，以研究神经血管动力学，为未来 研究，并将提供专业培训，以提高口头陈述和赠款写作 skills.

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.