Mechanisms of Vasomotion-mediated Perivascular Clearance in Cerebral Amyloid Angiopathy

项目摘要/摘要 标题项目：《脑淀粉样血管病血管运动介导的血管周围清除机制》 大脑中的血管在促进代谢废物的清除方面发挥着重要作用。 淀粉样蛋白β的血管周围清除障碍(Aβ)与脑组织的病理生理机制有关 淀粉样血管病(CAA)和阿尔茨海默病。然而，根本的未知，包括 血管周围清除的方向性和主要驱动力仍然存在，这阻碍了发展 旨在针对血管周围废物清除系统的治疗策略。此外，试验性的 在老鼠身上的观察在很大程度上仍然没有在人脑中得到探索。申请人之前的工作 发现血管运动的一个作用--血管平滑产生的小动脉缓慢自发振荡 肌细胞(SMCs)--作为血管周围清除的主要驱动力。这个项目将进一步放大 血管运动，并测试新的假设，即靶向血管SMCs可能提供一种有吸引力的方法 增强血管运动，从而促进血管周围Aβ的清除。该项目将使用CAA作为模型 疾病来验证这一假说，因为CAA的特点是血管Aβ逐渐沉积，受损 血管周围清除、SMC变性和血管功能障碍。该项目的目标是进一步 揭示血管运动介导的血管周围清除的生理学基础，以确定 血管Aβ积聚对血管运动和清除的影响，探讨低频增强的潜力 小动脉振荡作为一种干预策略成功清除脑中的β，并测量 低频血流动力学与人脑内液体流动之间的耦合。我们将使用翻译的 方法，利用清醒小鼠的光学成像技术结合直接光遗传刺激 血管SMCs，以及患有和不患有CAA的人的快速功能磁共振成像。成功 这些目标的完成将提高我们对血管运动介导的生理基础的理解 血管周围清除，并提供急需的概念验证数据，以支持调节的潜力 低频率小动脉振荡作为促进Aβ从脑中清除的早期干预策略。

Project Summary / Abstract Title project: “Mechanisms of vasomotion-mediated perivascular clearance in cerebral amyloid angiopathy” The blood vessels in the brain play an important role in facilitating clearance of metabolic waste products. Impaired perivascular clearance of amyloid β (Aβ) has been implicated in the pathophysiology of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease. However, fundamental unknows including the directionality and major driving forces of perivascular clearance remain, which has hampered the development of therapeutic strategies aimed at targeting the perivascular waste clearance system. Moreover, experimental observations in mice have remain largely unexplored in the human brain. Prior work from the applicant uncovered a role for vasomotion – slow spontaneous oscillations of arterioles generated by vascular smooth muscle cells (SMCs) – as a major driving force for perivascular clearance. This project will further zoom in on vasomotion and test the novel hypothesis that targeting vascular SMCs may provide an attractive approach to enhance vasomotion and thereby facilitate perivascular Aβ clearance. This project will use CAA as a model disease to test this hypothesis, as CAA is characterized by the gradual deposition of vascular Aβ, impaired perivascular clearance, SMC degeneration, and vascular dysfunction. The aims of this project are to further unravel the physiological basis of vasomotion-mediated perivascular clearance, to determine the effect of vascular Aβ accumulation on vasomotion and clearance, to explore the potential of enhancing low frequency arteriolar oscillations as an intervention strategy to successfully clear Aβ from the brain, and to measure the coupling between low frequency hemodynamics and fluid flow in the human brain. We will use a translational approach, utilizing optical imaging techniques in awake mice coupled with direct optogenetic stimulation of vascular SMCs, as well as fast functional MRI in human individuals with and without CAA. Successful completion of these aims will improve our understanding of the physiological basis of vasomotion-mediated perivascular clearance and provide much needed proof-of-concept data to support the potential of modulating low frequency arteriolar oscillations as an early intervention strategy to promote Aβ clearance from the brain.