Mechanisms of Vasomotion-mediated Perivascular Clearance in Cerebral Amyloid Angiopathy

脑淀粉样血管病中血管舒缩介导的血管周围清除机制

• 批准号: 10669786
• 负责人: Susanne Janneke Van Veluw
• 金额: $ 61.24万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669786
• 关键词: Abeta clearance; Acceleration; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Amyloid beta-Protein; Arteries; Automobile Driving; Blood Vessels; Blood capillaries; Brain; Calcium; Cell physiology; Cells; Cephalic; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrospinal Fluid; Cerebrovascular system; Chronic; Coupled; Coupling; Data; Dementia; Deposition; Dextrans; Disease; Disease model; Drainage procedure; Early Intervention; Elderly; Event; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genes; Hemorrhage; High Prevalence; Human; Image; Imaging Techniques; Immunotherapy; Impaired cognition; Impairment; Individual; Injections; Intercellular Fluid; Intervention; Label; Leptomeninges; Literature; Lobar; Measures; Mediating; Metabolic; Methods; Modeling; Mus; Nutrient; Oxygen; Pathway interactions; Patients; Pattern; Photic Stimulation; Physiological; Physiology; Play; Process; Property; Research; Resolution; Rest; Risk; Role; Severities; Smooth Muscle Myocytes; Speed; System; Techniques; Testing; Time; Tracer; Transgenic Mice; Translations; Vascular Diseases; Vascular Smooth Muscle; Visual; Waste Products; Work; abeta accumulation; abeta deposition; aging brain; arteriole; awake; blood oxygen level dependent; brain health; brain tissue; cerebrospinal fluid flow; clinical diagnosis; design; driving force; effective therapy; experimental study; fluid flow; hemodynamics; improved; in vivo; in vivo optical imaging; innovation; mouse model; neuroimaging; new therapeutic target; non-invasive imaging; novel; optical imaging; optogenetics; particle; preservation; prevent; single-cell RNA sequencing; solute; therapeutic development; transcriptomics; translational approach; two photon microscopy; vasomotion; wasting

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.

项目摘要/摘要

项目成果

Spontaneous vasomotion propagates along pial arterioles in the awake mouse brain like stimulus-evoked vascular reactivity.

自发血管舒缩沿着清醒小鼠大脑中的软脑膜小动脉传播，就像刺激引起的血管反应一样。

• DOI: 10.1177/0271678x231152550
• 发表时间: 2023
• 期刊: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
• 作者: Munting,LeonP;Bonnar,Orla;Kozberg,MarielG;Auger,CorinneA;Hirschler,Lydiane;Hou,StevenS;Greenberg,StevenM;Bacskai,BrianJ;vanVeluw,SusanneJ
• 通讯作者: vanVeluw,SusanneJ