ASTROCYTE-SECRETED PROTEINS AS MODULATORS OF NEURODEGENERATION IN DOWN SYNDROME AND ALZHEIMERS DISEASE - PR…

Assistance award details

Assistance award identifier

ASST_NON_R00AG081536_075

FAIN

R00AG081536

Recipient

RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$493,020

Period

Jun 1, 2023 – Feb 29, 2028

Fiscal year

2025

Place of performance state

VA

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

ASTROCYTE-SECRETED PROTEINS AS MODULATORS OF NEURODEGENERATION IN DOWN SYNDROME AND ALZHEIMERS DISEASE - PROJECT SUMMARY/ABSTRACT DOWN SYNDROME (DS) IS A NEURODEVELOPMENTAL DISORDER CAUSED BY TRISOMY OF CHROMOSOME 21, AND WITH AGE A MAJORITY OF DS PATIENTS DEVELOP NEUROPATHOLOGICAL HALLMARKS ASSOCIATED WITH ALZHEIMER’S DISEASE (AD), INCLUDING AMYLOID PLAQUE DEPOSITION AND ASTROGLIOSIS, AS WELL AS CLINICAL DEMENTIA (COOCCURRENCE OF DS WITH AD IS DS-AD). AMYLOID PRECURSOR PROTEIN (APP) MUTATIONS ARE LINKED TO AD, AND DS PATIENTS HAVE TRIPLICATION OF THE APP GENE, SUGGESTING THIS AS A CONTRIBUTING FACTOR TO THE OVERLAPPING PATHOLOGY. RESEARCH SUGGESTS ASTROCYTES ARE REGULATORS OF BOTH DS AND AD DISEASE PROGRESSION. ASTROCYTES MODULATE SYNAPSES THROUGH THE RELEASE OF SECRETED PROTEINS, AND RECENT WORK SUGGESTS THAT ASTROCYTE PROTEIN SECRETION IS DYSREGULATED IN BOTH DS AND AD. THE ALLEN LAB IDENTIFIED >700 ASTROCYTE-SECRETED PROTEINS DYSREGULATED IN THE TS65DN MOUSE MODEL OF DS AT NEONATAL TIMEPOINTS. OF INTEREST, SECRETION OF THE PRO-GROWTH PROTEIN PLEIOTROPHIN (PTN) WAS >4X DOWN-REGULATED FROM TS65DN ASTROCYTES, AND SUBSEQUENT INVESTIGATIONS OF PTN KNOCKOUT MICE REVEALED THAT THEY PHENOCOPY TS65DN MICE IN MANY ASPECTS, INCLUDING DECREASED DENDRITE LENGTH AND SPINE DENSITY. SINGLE NUCLEUS RNA- SEQUENCING STUDIES SHOW THAT SUBSETS OF “DISEASE-ASSOCIATED” ASTROCYTES IN AD DOWN-REGULATE TRANSCRIPTS ENCODING FOR MANY PRO-SYNAPTOGENIC FACTORS, INCLUDING PTN. THE MAIN HYPOTHESES OF THIS PROPOSAL ARE THAT: 1) A NETWORK OF OVERLAPPING ASTROCYTE-SECRETED PROTEINS IS ALTERED IN DS-AD AND AD, AND 2) DECREASED PTN SECRETION FROM ASTROCYTES CONTRIBUTES TO DISEASE PROGRESSION IN DS-AD AND AD. THIS PROPOSAL TAKES AN UNBIASED APPROACH TO CHARACTERIZE CHANGES IN THE ASTROCYTE SECRETOME IN DS-AD AND AD MOUSE MODELS, AS WELL AS A TARGETED APPROACH TO INVESTIGATE THE POTENTIAL FOR PTN TO RESCUE NEUROPATHOLOGICAL PHENOTYPES. AIM 1/K99 UTILIZES BIOTIN- MEDIATED PROXIMITY LABELING (AN