Mechanisms of vasomotion-mediated perivascular clearance in cerebral amyloid angiopathy

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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.