RF1AG062738

PERICYTE STRUCTURAL PLASTICITY AND CEREBROVASCULAR HEALTH IN A MODEL OF TYPE-1 CEREBRAL AMYLOID ANGIOPATHY - PROJECT SUMMARY ALZHEIMER’S DISEASE (AD) IS A MAJOR CAUSE OF COGNITIVE DECLINE AND POSES AN INCREASING SOCIO-ECONOMIC BURDEN. CEREBRAL SMALL VESSEL DISEASE (CSVD) CONTRIBUTES TO AD PATHOLOGY, PARTLY BY INDUCING NEURODEGENERATION THROUGH HYPOPERFUSION. WHILE RESEARCH HAS PRIMARILY FOCUSED ON CEREBRAL ARTERIES AND ARTERIOLES, CAPILLARIES MAKE UP OVER 90% OF BRAIN VASCULATURE AND CONTRIBUTE SIGNIFICANTLY TO OVERALL RESISTANCE OF CEREBRAL BLOOD FLOW. THE MECHANISMS OF CAPILLARY DYSFUNCTION IN AD REMAIN LARGELY UNDEREXPLORED. PERICYTES, WHICH ARE MURAL CELLS LINING BRAIN CAPILLARIES, ARE HIGHLY SUSCEPTIBLE TO INJURY DURING AD. OUR PRIOR RESEARCH DEMONSTRATED THAT PERICYTE COVERAGE IS ESSENTIAL FOR MAINTAINING CAPILLARY BLOOD FLOW AND STRUCTURE. USING TWO-PHOTON IMAGING IN MICE, WE SHOWED THAT PERICYTE LOSS LEADS TO CAPILLARY RAREFACTION AND POOR BLOOD DISTRIBUTION, OCCURRING EVEN IN THE ABSENCE OF BLOOD- BRAIN BARRIER LEAKAGE. BUILDING ON THESE FINDINGS, THIS PROJECT INVESTIGATES A FORM OF CSVD KNOWN AS TYPE-1 CEREBRAL AMYLOID ANGIOPATHY (CAA), WHERE AMYLOID Β (AΒ) DEPOSITS PREFERENTIALLY ON CAPILLARIES. PRELIMINARY STUDIES IN A MOUSE MODEL OF TYPE-1 CAA (TG-SWDI MICE) REVEALED SPONTANEOUS PERICYTE LOSS IN CAPILLARY-SIZED VESSELS DRAINING INTO CORTICAL VENULES, REFERRED TO AS PERI-VENOUS CAPILLARIES. THIS LOSS WAS ASSOCIATED WITH CAPILLARY REGRESSION AND REDUCED BLOOD FLOW. OUR CENTRAL HYPOTHESIS IS THAT AΒ INDUCES STRONG INFLAMMATORY RESPONSES IN PERI-VENOUS CAPILLARIES, LEADING TO PERICYTE LOSS IN THIS VASCULAR ZONE. THIS DISRUPTION OF BLOOD FLOW CAUSES VASCULAR REGRESSION, IMPAIRING DRAINAGE FROM THE BRAIN. WE ALSO HYPOTHESIZE THAT THIS EFFECT MAY BE REVERSIBLE WITH PHARMACOLOGICAL STRATEGIES AIMED AT PROMOTING PERICYTE REMODELING. IN AIM 1, WE WILL IDENTIFY VULNERABLE BRAIN REGIONS IN TG-SWDI MICE BY MAPPING THE SPATIOTEMPORAL RELATIONSHIPS BETWEEN PERICYTE LOSS, CAPILLARY REGRESSION, AΒ DEPOSITION, AND INFLAMMATION ACROSS THE ENTIRE BRAIN USING LIGHT-SHEET IMAGING. IN AIM 2, WE WILL UTILIZE TWO-PHOTON IMAGING TO ASSESS THE EFFECTS OF SPONTANEOUS AND OPTICALLY INDUCED PERICYTE LOSS ON CAPILLARY FUNCTION IN VIVO, FOCUSING ON BLOOD FLOW, CAPILLARY STRUCTURE, AND INFLAMMATION IN THE CEREBRAL CORTEX. IN AIM 3, WE WILL INVESTIGATE WHETHER MODULATING PDGFRΒ CAN ENHANCE PERICYTE COVERAGE IN TG-SWDI MICE, BUILDING ON AN UNEXPECTED FINDING THAT THE PULSED DELIVERY OF THE PDGFRΒ INHIBITOR SU16F LEADS TO A COMPENSATORY INCREASE IN PERICYTE REMODELING IN VIVO. WE WILL DETERMINE IF THIS THERAPEUTIC STRATEGY PROMOTES A REGENERATIVE VASCULAR PHENOTYPE AND REDUCES INFLAMMATION, ULTIMATELY IMPROVING PERICYTE COVERAGE AND CAPILLARY FUNCTION. OVERALL, THESE STUDIES, CONDUCTED BY A MULTIDISCIPLINARY TEAM USING INNOVATIVE TECHNIQUES AND CONCEPTS, WILL GENERATE VALUABLE INSIGHTS INTO PERICYTE LOSS IN THE TG-SWDI MODEL, CLARIFY THE ETIOLOGY AND CONSEQUENCES OF CAPILLARY PATHOLOGY WITH AΒ BURDEN, AND TEST POTENTIAL THERAPIES FOR PROMOTING PERICYTE REMODELING AND BALANCED CAPILLARY PERFUSION.

Seattle Children's Hospital

NOT APPLICABLE

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Washington United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)