DYSREGULATED CHOLESTEROL METABOLISM IN ALZHEIMER'S DISEASE ASTROCYTES: INVESTIGATING CONTRIBUTIONS TO NEURO…

Assistance award details

Assistance award identifier

ASST_NON_K00AG104085_075

FAIN

K00AG104085

Recipient

REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$81,238

Period

Jul 1, 2023 – Mar 31, 2030

Fiscal year

2026

Place of performance state

CA

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

DYSREGULATED CHOLESTEROL METABOLISM IN ALZHEIMER'S DISEASE ASTROCYTES: INVESTIGATING CONTRIBUTIONS TO NEURONAL DYSFUNCTION - PROJECT SUMMARY THE ABSENCE OF EFFECTIVE THERAPIES TO SLOW OR PREVENT PROGRESSION HAVE MADE ALZHEIMER’S DISEASE (AD) A GLOBAL HEALTH CRISIS. INFLAMMATION, NEURONAL DYSFUNCTION, AND EVENTUAL NEURONAL LOSS ARE HALLMARKS OF AD. CHOLESTEROL METABOLISM IS ALSO IMPLICATED IN AD AND OTHER NEURODEGENERATIVE DISEASES. FOR EXAMPLE, ACCUMULATION OF LIPID DROPLETS THAT STORE INTRACELLULAR LIPIDS ARE OBSERVED IN AD BRAINS. CHOLESTEROL ACTS AS A SIGNALING MOLECULES AND IS AN ESSENTIAL COMPONENT OF BIOLOGICAL MEMBRANES. NOTABLY, CHOLESTEROL LEVELS IN THE PRESYNAPTIC AND POSTSYNAPTIC COMPARTMENTS INFLUENCE SYNAPTIC TRANSMISSION. THUS, CHANGES TO CHOLESTEROL METABOLISM COULD DIRECTLY INDUCE NEURONAL DYSFUNCTION AND OTHER AD-ASSOCIATED PATHOLOGY. WHILE MOST RESEARCH FOCUSES ON NEURONS, NON-NEURONAL GLIAL CELLS ARE ESSENTIAL IN REGULATING NEURONAL FUNCTION AND MAINTAINING BRAIN HOMEOSTASIS. ASTROCYTES ARE A CLASS OF GLIAL CELL THAT INTERACT WITH SYNAPSES, BLOOD VESSELS, AND OTHER GLIAL CELLS, PLAYING ESSENTIAL ROLES IN THE REGULATION OF SYNAPTIC CONNECTIVITY AND FUNCTION THROUGHOUT LIFE. RECENT STUDIES SUGGEST THAT CHANGES TO ASTROCYTES ARE POTENTIAL DRIVERS OF AD PATHOLOGY. ASTROCYTES HAVE DECREASED PHYSIOLOGICAL FUNCTIONS AND RELEASE INFLAMMATORY FACTORS IN DISEASE STATES. AS THE MAIN PRODUCERS OF CHOLESTEROL IN THE BRAIN, CHOLESTEROL DYSREGULATIONS IN AD COULD ALSO BE PRIMARILY DRIVEN BY CHANGES IN ASTROCYTE METABOLISM. HOWEVER, IT IS STILL UNCLEAR TO WHAT EXTENT CHOLESTEROL METABOLISM IS DYSREGULATED IN AD ASTROCYTES AND WHAT SPECIFIC GENES COULD BE TARGETED TO REVERSE THESE CHANGES. THE OVERALL GOAL OF MY DISSERTATION AND POST-DOCTORAL RESEARCH IS TO CHARACTERIZE CHOLESTEROL METABOLISM IN ASTROCYTES IN THE CONTEXT OF AD. PRELIMINARY DATA IN AIM 1 DEMONSTRATES MY ABILITY TO USE HUMAN STEM CELL MODELS TO STUDY INTRINSIC CHANGES IN ASTROCYTES DERIVED FROM