Project Grant R01AG085666

ATYPICAL ASTROCYTES IN AGING AND ALZHEIMER'S DISEASE - SUMMARY. ASTROCYTES CONTROL NEUROTRANSMISSION, CONTRIBUTE TO THE BLOOD-BRAIN-BARRIER (BBB), AND SHAPE INFLAMMATORY RESPONSES. IN HEALTHY AGING, MANY ASPECTS OF ASTROCYTE FUNCTION ARE ALTERED BUT WHAT DRIVES AGING-RELATED CHANGES IS NOT WELL UNDERSTOOD. HERE, WE PRESENT EXCITING PRELIMINARY DATA THAT DURING NORMAL AGING, ASTROCYTES TAKE ON A NOVEL PHENOTYPE IN WHICH PROGRESSIVELY MORE ASTROCYTES LOSE THE EXPRESSION OF KEY FUNCTIONAL PROTEINS. WE REFER TO THESE AS ATYPICAL ASTROCYTES (ATAS). ATAS LACK EXPRESSION OF EXCITATORY AMINO ACID TRANSPORTERS (EAATS: GLT-1 AND GLAST), THAT REMOVE GLUTAMATE FROM THE EXTRACELLULAR SPACE, KIR4.1, WHICH MEDIATES EXTRACELLULAR POTASSIUM (K+) BUFFERING, AND AQUAPORIN-4 (AQP-4), WHICH HELPS CLEAR A FROM THE BRAIN. THESE CHANGES OCCUR ON A CELL-BY-CELL BASIS, WITH INDIVIDUAL ASTROCYTES EXPRESSING MINIMAL EAAT, KIR4.1, AND AQP-4, WHILE NEIGHBORING ASTROCYTES REMAIN NORMAL. ATAS DO NOT APPEAR TO BE REACTIVE ASTROCYTES AS THEY LACK ELEVATED GFAP EXPRESSION AND HAVE NORMAL ASTROCYTE MORPHOLOGY. PRELIMINARY IGLUSNFR AND ASTROCYTE ELECTROPHYSIOLOGY DATA SUGGEST THAT GLUTAMATE AND K+ HOMEOSTASIS IS COMPROMISED IN AREAS WHERE ATAS ARE ABUNDANT. WHAT CAUSES ATA TO FORM IS NOT KNOWN, BUT PUBLISHED AND PRELIMINARY STUDIES SUGGEST ATAS ARE ASSOCIATED WITH VASCULAR STRUCTURES AND ARE FOUND IN AREAS OF BLOOD-BRAIN-BARRIER (BBB) COMPROMISE. OUR PRELIMINARY DATA ALSO SUGGESTS THAT ATAS ARE FOUND IN THE AGING HUMAN BRAIN AND ARE MORE ABUNDANT IN THE APPNL-G-F MODEL OF AD, AS COMPARED TO WT MICE. THEREFORE, WE HYPOTHESIZE THAT AGE-ASSOCIATED VASCULAR DYSFUNCTION DRIVES THE FORMATION OF ATAS, DISRUPTING ASTROCYTE FUNCTION AND CONTRIBUTING TO SYNAPTIC AND AD-RELATED PATHOLOGY. ASTROCYTE DYSFUNCTION OCCURS LATE IN AD PROGRESSION, BUT HOW ASTROCYTES CONTRIBUTE TO EARLY AD PATHOLOGY IS NOT WELL UNDERSTOOD. WE SUSPECT ATAS OCCUR EARLY IN AD PROGRESSION AND CONTRIBUTE TO DIVERSE AD DISEASE MECHANISMS. EVIDENCE SUPPORTS THAT ABERRANT GLUTAMATE SIGNALING CONTRIBUTES TO AD PROGRESSION. DISRUPTED AQP-4 EXPRESSION IS A HALLMARK OF AD AND ASSOCIATED WITH REDUCED A CLEARANCE. VASCULAR DYSFUNCTION IS AN AD RISK FACTOR AND ASTROCYTES CONTRIBUTE TO BBB INTEGRITY. TO EXAMINE ATAS IN A MODEL OF AD, WE CHOSE THE APPNL-G-F MICE DUE TO EARLY ONSET OF ELEVATED SOLUBLE A AND PLAQUES OVERLAPPING WITH THE NORMAL DEVELOPMENT OF ATAS, WITHOUT APP OVEREXPRESSION. IF OUR HYPOTHESIS IS CORRECT, ATAS MAY BE A CENTRAL PLAYER IN AGING AND AD-RELATED PATHOLOGIES LINKING VASCULAR DYSFUNCTION TO SYNAPTIC AND A PATHOLOGY. IN THIS PROPOSAL WE WILL DETERMINE 1) WHAT ARE THE MOLECULAR AND CELLULAR PHENOTYPES OF ATAS IN THE AGING AND AD BRAIN?, 2) DO ATAS DISRUPT SYNAPTIC FUNCTION, IONIC HOMEOSTASIS, AND A HANDLING?, AND 3) DOES BBB DYSFUNCTION CONTRIBUTE TO THE GENERATION OF ATAS? WHEN COMPLETE, WE WILL KNOW THE MOLECULAR AND CELLULAR PROPERTIES OF AGE-ASSOCIATED ATAS, THEIR EFFECTS ON ASTROCYTE-MEDIATED HOMEOSTASIS, AND THEIR RELATIONSHIP WITH BBB DYSFUNCTION. IF ATAS MEDIATE ASTROCYTE-NEURON DYSFUNCTION CAUSED BY AGE-RELATED VASCULAR PATHOLOGY, IT WILL REPRESENT AN ENTIRELY NEW AVENUE TO PURSUE FOR TREATING AD AND OTHER AGE-RELATED NEUROLOGICAL DISEASE.