Project Grant RF1AG079157

DISRUPTED LIPID METABOLISM IN ALZHEIMER'S DISEASE - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS THE MOST PREVALENT FORM OF DEMENTIA AFFECTING APPROXIMATELY 50 MILLION PEOPLE WORLDWIDE. LARGE VOLUMES OF CLINICAL EVIDENCE HAVE REVEALED ALTERATIONS IN LIPID METABOLISM EMERGING IN EARLY STAGES OF THE DISEASE. MOREOVER, A VARIETY OF LIPID-RELATED GENES AND PERIPHERAL LIPID ABNORMALITIES HAVE BEEN IDENTIFIED AS SIGNIFICANT AD RISK MODIFIERS. HOWEVER, THE PRECISE MECHANISMS BY WHICH DISRUPTED LIPID METABOLISM IS INITIATED, AND HOW IT SUBSEQUENTLY CONTRIBUTES TO AD PATHOLOGIES, REMAIN ELUSIVE. AS THE ESSENTIAL BUILDING BLOCKS FOR MOST LIPID SPECIES, THE HOMEOSTASIS OF FATTY ACID (FA) IS KEY TO THE COMPOSITION AND FUNCTIONALITY OF BRAIN LIPIDS. WHILE THE SYNTHESIS, TRANSPORT AND UTILIZATION OF FAS INVOLVE ALL BRAIN CELL TYPES, THE DEGRADATION OF FAS OCCURS PREDOMINANTLY IN ASTROCYTES VIA MITOCHONDRIAL FA B-OXIDATION (FAO) AND OXIDATIVE PHOSPHORYLATION (OXPHOS). THIS UNIQUE METABOLIC FEATURE OF ASTROCYTES, ALONG WITH THE EARLY OCCURRENCE OF THEIR REACTIVE TRANSFORMATION IN AD BRAINS, STRONGLY SUGGESTS A VITAL ROLE OF ASTROCYTES IN AD- ASSOCIATED LIPID DYSHOMEOSTASIS AND RAISES THE QUESTION AS TO WHETHER AND HOW DISRUPTED ASTROCYTIC FA DEGRADATION PROMOTES DISEASE ONSET AND PROGRESSION. OUR RECENT WORK DEMONSTRATES THAT LOSS OF FA DEGRADATION BY ASTROCYTIC MITOCHONDRIA IS SUFFICIENT TO TRIGGER LIPID DROPLET ACCUMULATION AND REACTIVE ASTROGLIOSIS FOLLOWED BY PROGRESSIVE, AD-RESEMBLING NEUROINFLAMMATION, NEURODEGENERATION AND COGNITIVE IMPAIRMENT. WE FURTHER REPORTED THAT REDUCED ASTROCYTIC FA DEGRADATION OCCURS IN EARLY STAGES OF AN AMYLOIDOSIS MODEL OF AD. RESEARCH PROPOSED HEREIN WILL TEST OUR HYPOTHESIS THAT B-AMYLOID (AB)-DRIVEN METABOLIC REPROGRAMMING OF ASTROCYTES IMPAIRS FA DEGRADATION AND TRIGGERS LIPID DYSHOMEOSTASIS AND ASTROCYTE REACTIVITY, WHICH CONSEQUENTLY DRIVE OR EXACERBATE PROTEINOPATHIES (AB AND TAU) AND OTHER AD PATHOLOGIES. WE FURTHER HYPOTHESIZE THAT ENHANCING ASTROCYTIC FA DEGRADATION ALLEVIATES THESE AD HALLMARKS AND COGNITIVE DEFICIT BY RESTORING BRAIN LIPID HOMEOSTASIS AND SUPPRESSING DETRIMENTAL TRANSFORMATION OF ASTROCYTE. WE WILL FIRST DETERMINE WHEN, WHERE, AND HOW EARLY AMYLOID PATHOLOGY METABOLICALLY REPROGRAMS ASTROCYTES TOWARDS AD- ASSOCIATED TRANSFORMATION USING AN AMYLOIDOSIS MODEL OF AD. UTILIZING OUR VALIDATED MODEL OF ASTROCYTIC FA DEGRADATION DEFICIT, WE WILL DETERMINE THE MECHANISMS BY WHICH IMPAIRED ASTROCYTIC LIPID DEGRADATION DRIVES OR EXACERBATES AD PATHOLOGIES. LASTLY, WE WILL TEST WHETHER SELECTIVE ENHANCEMENT OF ASTROCYTIC FA DEGRADATION CAN AMELIORATE LIPID DYSHOMEOSTASIS, NEUROINFLAMMATION, AD PROTEINOPATHIES, AND COGNITIVE IMPAIRMENT IN BOTH AMYLOID AND TAU MODELS. PROJECTED OUTCOMES FROM THIS RESEARCH WILL TEST THE EARLY, AND POTENTIALLY CENTRAL, ROLE OF LIPID DYSREGULATION AND ASTROCYTE REACTIVITY IN DRIVING AD PATHOLOGIES. TRANSLATIONALLY, THIS RESEARCH COULD ALSO PAVE THE WAY TO NOVEL ASTROCYTE-SPECIFIC AD THERAPEUTICS BY SUSTAINING OR RESTORING EFFICIENT LIPID TURNOVER IN THE DEGENERATING BRAIN.