Project Grant F31AG104842

SOCIAL ISOLATION CONTRIBUTES TO AD PATHOGENESIS AND RISK BY REDUCING CORTICAL BLOOD FLOW - PROJECT SUMMARY/ABSTRACT ALZHEIMER'S DISEASE (AD) IS A DEBILITATING NEURODEGENERATIVE DISEASE CHARACTERIZED BY RAPID LOSS OF COGNITIVE FUNCTION DUE TO ABERRANT ACCUMULATION OF THE NEUROTOXIC PROTEINS AMYLOID-BETA (AB) AND HYPERPHOSPHORYLATED TAU TANGLES. THERE IS NO CURE FOR AD, AND TREATMENTS ARE LIMITED. AS THIS DISEASE IS PRIMARILY DIAGNOSED LATER IN LIFE, RESEARCH HAS FOCUSED ON EARLY INTERVENTION, PREVENTION, AND DIAGNOSTIC PROCEDURES. INDEED, UP TO 45% OF AD CASES COULD BE PREVENTED THROUGH MODIFIABLE LIFESTYLE FACTORS. ONE SUCH FACTOR, SOCIAL ISOLATION (SI), IS RECOGNIZED BY THE NIH AS A MAJOR HEALTH HAZARD, BUT THE MECHANISMS WHEREBY SI CONTRIBUTES TO AD ARE POORLY UNDERSTOOD. HERE, WE HAVE IDENTIFIED THAT REDUCED CEREBRAL BLOOD FLOW (CBF), ONE OF THE EARLIEST BIOMARKERS FOR AD, IS A SHARED CHARACTERISTIC BETWEEN SI AND AD. AQUAPORIN-4 (AQP4), A WATER CHANNEL PRIMARILY EXPRESSED BY ASTROCYTES AT THEIR VASCULAR ASSOCIATED ENDFEET, HAS FOUND GROWING ATTENTION IN AD RESEARCH. INDEED, SEVERAL STUDIES HAVE IDENTIFIED MISLOCALIZATION OF AQP4 AWAY FROM ASTROCYTE ENDFEET, AND DELETION OF AQP4 RESULTS IN ABERRANT AB ACCUMULATION. NOTABLY, AQP4 IS MOST HIGHLY EXPRESSED AT THE PIAL SURFACE, DIRECTLY BELOW THE MAJOR ARTERIES THAT ACCOUNT FOR THE MAJORITY OF CORTICAL INFLOW. IN THE CONTEXT OF SI, WE FOUND THAT 4 MONTHS OF SI IN WILDTYPE (WT) MALE MICE RESULTED IN A MARKED REDUCTION IN PIAL AQP4 EXPRESSION. NOTABLY, WE HAVE IDENTIFIED IN OUR ANIMAL MODEL THAT THIS REGION, THE ASTROCYTE/MENINGEAL VASCULAR INTERFACE, ALSO REPRESENTS THE DENSEST ACCUMULATION OF AB VERSUS ANYWHERE ELSE IN THE BRAIN, PRIMARILY IN THE FORM OF VASCULAR PLAQUES OR CEREBRAL AMYLOID ANGIOPATHY (CAA). THE LEVEL OF THIS CAA CORRELATES WITH REDUCTIONS IN CBF IN OUR MODEL OF AD. ALTOGETHER, OUR FINDINGS SUGGEST AT THE SITE OF THE ASTROCYTE/MENINGEAL VASCULAR INTERFACE, 1) AQP4 FACILITATES CSF FLOW INTO THE PARENCHYMA, 2) CREATES A DIRECTIONAL FLOW RESULTING IN WASTE ACCUMULATION, I.E. AB, TOWARDS THE PIAL SURFACE, 3) LEADS TO HEIGHTENED AB ACCUMULATION AROUND BLOOD VESSELS, CHOKING CORTICAL BLOOD INFLOW. HOW SI CONTRIBUTES TO THIS PHENOMENON IS UNKNOWN. THUS, WE WILL FIRST COMPARE SI WT AND AD MICE CBF THROUGH LASER SPECKLE CONTRAST IMAGING, MENINGEAL AQP4 EXPRESSION THROUGH IMMUNOHISTOCHEMISTRY, AND MENINGEAL AB ACCUMULATION THROUGH IMMUNOHISTOCHEMISTRY AND INTRAPERITONEAL INJECTIONS OF THE BLOOD BRAIN BARRIER PERMEABLE AB SPECIFIC DYE METHOXY-X04. WE WILL ASSESS WHETHER PIAL AQP4 IS NECESSARY AND SUFFICIENT TO DRIVE CBF AND AB ALTERATIONS IN AD AND SI MICE THROUGH VIRAL MANIPULATIONS OF SURFACE AQP4. SUCCESSFUL COMPLETION OF THIS PROJECT MAY PROVIDE INSIGHT INTO HOW SI CONTRIBUTES TO AD PROGRESSION, AND PROVIDE A NOVEL THERAPEUTIC AVENUE FOR THE TREATMENT OF AD. THE APPROACHES EMPLOYED IN THIS PROPOSAL WILL PROVIDE A BREADTH OF EXPERIMENTAL TECHNIQUES INCLUDING SURGICAL TECHNIQUES AND COMPLEX IMAGE ANALYSIS. TRAINING FOR THESE PROCEDURES WILL TAKE PLACE IN THE SPONSOR'S LABORATORY. THROUGHOUT THE FELLOWSHIP, PROFESSIONAL DEVELOPMENT WILL OCCUR THROUGH SEMINARS, COURSEWORK, AND JOURNAL CLUB'S ASSOCIATED WITH VIRGINIA TECH, AND LOCAL AND NATIONAL CONFERENCES TO PREPARE THE PI FOR A CAREER AS AN INDEPENDENT RESEARCHER.