Defining the mechanisms by which MS4A4A regulates TREM2 in Alzheimer disease

2018 Pilot Project Read More

Investigators

Principal Investigator: Celeste Karch (WashU Psychiatry)
Collaborator: Thomas Brett (WashU Medicine), Laura Piccio (WashU Neurology)

Description

Alzheimer’s disease is the most common neurodegenerative disease; however, there are currently no effective means of prevention or treatment. Human genetic and animal models have recently implicated the TREM2 gene in microglial function and in AD pathogenesis. In this proposal, we will study the mechanism by which a novel regulator of TREM2 influences AD risk using molecular and biochemical approaches in stem cell models. The results of this project will provide the mechanistic framework needed to develop treatments that restore or enhance TREM2 functions in order to prevent neurodegenerative disease.

Grants and Awards

“Brain Single-nuclei and iPS-derived cells transcriptomic analysis to define the contribution of neuronal and glial pathw”
NIH/NIA 1R56AG067764 (PI, Harari)
Public Health Relevance Statement, NARRATIVE: Alzheimer’s disease (AD) is the most common neurodegenerative disease, but currently there is no effective means of prevention or treatment. Genetic mutations and risk variants provide support to the amyloid cascade hypothesis, cholesterol metabolism and immune response in the etiology of AD. In this project, we will generate a detailed molecular atlas of AD brains carriers of pathogenic mutations, risk variants, non-carrier AD, and neuropath-free controls to determine the specific pathways and molecular networks disrupted in the distinct brain cell-types that lead to AD.

“Defining the Mechanisms by Which MS4A Genes Regulate TREM2 in Alzheimer Disease”
NIH/NIA 1R01AG062734 (PI, Karch)
NIH/NIA 5R01AG062734 (PI, Karch)
Public Health Relevance Statement, Narrative: Alzheimer’s disease is the most common neurodegenerative disease; however, there are currently no effective means of prevention or treatment. Human genetic and animal models have recently implicated the TREM2 gene in microglial function and in AD pathogenesis. In this proposal, we will study the mechanism by which a novel regulator of TREM2 influences AD risk using human genomic and stem cell approaches.

“Molecular Mechanisms of the Central Regulator of TREM2 Dysfunction”
Chan Zuckerberg Initiative Neurodegeneration Challenge Network

“Novel MS4A4A-Targeting Therapeutics for Alzheimer’s Disease” (page 4)
Edward N. and Della L. Thome Memorial Foundation Awards Program in Alzheimer’s Disease Drug Discovery Research

 

Updated April 27, 2021

Investigators

Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty on this team, click below.

Celeste Karch

Laura Piccio