GPCR-DEPENDENT MICROGLIAL FUNCTION IN ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT: ALZHEIMER'S DISEASE (…

Assistance award details

Assistance award identifier

ASST_NON_R00AG081694_075

FAIN

R00AG081694

Recipient

SAINT LOUIS UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$249,000

Period

Dec 1, 2023 – Mar 31, 2029

Fiscal year

2026

Place of performance state

MO

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

GPCR-DEPENDENT MICROGLIAL FUNCTION IN ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT: ALZHEIMER'S DISEASE (AD) IS A DEVASTATING NEURODEGENERATIVE DISEASE WITH VIRTUALLY NO THERAPEUTIC OPTIONS TO REVERSE ITS PATHOLOGY. GLIAL CELLS, INCLUDING MICROGLIA, PLAY CRITICAL ROLES IN BRAIN HOMEOSTASIS AND DISEASE PROGRESSION. GPR56 (ALSO CALLED ADGRG1 ), AN ADHESION G PROTEIN-COUPLED RECEPTOR (AGPCR), IS ONE OF THE CRITICAL GENES THAT DEFINE TRUE MICROGLIA: GPR56 IS ONLY EXPRESSED IN YOLK SAC-DERIVED MICROGLIA BUT NOT IN FETAL LIVER- AND BONE MARROW-DERIVED MICROGLIA-LIKE CELLS, EVEN AFTER LONG-TERM ADAPTATION IN THE CNS IN VIVO. IMPORTANTLY, A RECENT STUDY FROM MATHYS ET AL. SHOWED THAT GPR56 IS ONE OF THE FIVE GENES UPREGULATED IN MICROGLIA IN INDIVIDUALS DYING WITH EARLY-STAGE AD COMPARED TO THOSE WITH NO PATHOLOGY OR LATE-STAGE AD. IMPORTANTLY, THEIR DATA WAS GENERATED FROM PARTICIPANTS IN A COMMUNITY-BASED COHORT STUDY, THE RELIGIOUS ORDER STUDY (ROS)/RUSH MEMORY AND AGING PROJECT (MAP), COLLECTIVELY KNOWN AS ROSMAP. OF THOSE AUTOPSIED, THE MEAN AGE WAS 89 YEARS. THIS OBSERVATION RAISES THE POSSIBILITY THAT INDIVIDUALS WITH UPREGULATED MICROGLIAL GPR56 SURVIVED TO ADVANCED AGE WITH MILD AD PATHOLOGY. TO INVESTIGATE THE UNEXPLORED FUNCTION OF MICROGLIAL GPR56 IN AD PROGRESSION, WE GENERATED A NEW AD MOUSE MODEL, 5XFAD;GPR56 ;CX3CR1-CRE'1-(AD-CKO) AND 5XFAD;GPR56+1';CX3CR1-CRE+1 - (AD-CONTROL). OUR PRELIMINARY SHOWED: (1) A SIGNIFICANT REDUCTION IN THE NUMBER OF MICROGLIA ASSOCIATED WITH AMYLOID PLAQUES, (2) A DRASTIC INCREASE IN PLAQUE BURDEN, (3) A REDUCTION IN NEUNPOSITIVE NEURONS, AND (4) MORE SEVERE DENDRITIC DYSTROPHY IN AD-CKO MOUSE BRAINS COMPARED TO AD-CONTROLS. TAKEN TOGETHER, I HYPOTHESIZE THAT MICROG/IAL GPR56 LIMITS AD PATHOLOGICAL PROGRESSION IN BOTH AD MOUSE MODELS AND HUMAN PATIENTS. TO TEST THIS HYPOTHESIS, I WILL ADDRESS THE FOLLOWING AIMS: AIM 1 IS TO INVESTIGATE THE ROLE OF MICROGLIAL GPR56 IN RESTRICTING AD PROGRESSION IN THE MOUSE MODEL; AIM 2 IS