Indiana University
Stark Neuroscience Research Institute
Dr. Lamb’s laboratory works on the basic science of Alzheimer’s disease, with a focus on: genetic modifiers identified from mouse and human studies; animal models of Alzheimer’s disease (including Director of the NIH-Funded Model Organism Development and Evaluation for Late-onset Alzheimer’s Disease program, MODEL-AD); microglia and neuronal-microglial communication in the development and progression of Alzheimer’s pathologies; traumatic brain injury as an environmental modifier for the development of Alzheimer’s pathologies; and Alzheimer’s disease drug discovery as Co-Director of the NIH-Funded IU School of Medicine/Purdue UniversityTarget Enablement to Advance Therapy Development for Alzheimer’s Disease (TREAT-AD) Center.
Presenter of 2 Presentations
IDENTIFICATION, CHARACTERIZATION, AND THERAPEUTIC TARGETING OF NOVEL MICROGLIAL PATHWAYS UNDERLYING ALZHEIMER’S DISEASE
Session Name
Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE PLENARY: 115-117
Lecture Time
10:25 AM - 10:40 AM
Presenter
Abstract
Abstract Body
Objectives: Alzheimer’s disease (AD) is noted for a robust microglial response. Recent genetic studies have identified several genetic risk variants that are predominantly expressed in microglia and associated with innate immunity. Among these risk genes is phospholipase C gamma 2 (PLCG2), a key regulatory hub for immune signaling. The hypermorphic P522R variant of PLCG2 has been reported to confer protection against AD. We have identified the less active M28L variant as a novel PLCG2 variant associated with elevated AD risk. Our aims were to examine the role of PLCG2 in AD and investigate mechanisms discriminating divergent effects of PLCG2 variants on AD risk.Methods: RNA-Seq data from human brains was queried to determine the role of PLCG2 in AD. To ascertain if PLCG2 risk variants alter microglial responses to amyloid plaques, we generated mice bearing the M28L risk or the P522R protective PLCG2 variant, all
crossed onto the 5xFAD murine model of AD.
Methods: RNA-Seq data from human brains was queried to determine the role of PLCG2 in AD. To ascertain if PLCG2 risk variants alter microglial responses to amyloid plaques, we generated mice bearing the M28L risk or the P522R protective PLCG2 variant, all
crossed onto the 5xFAD murine model of AD.
Results: PLCG2 expression was upregulated in AD brains and correlated with amyloid plaque density. PLCG2 gene expression was associated with pathways related to inflammatory response. Similar results were observed in 5xFAD mice. Primary murine microglia with the M28L variant of PLCG2 showed reduced uptake capacity of amyloid. PLCG2 variants affected plaque pathology, altered microglial phenotypes, and drove distinct transcriptional phenotypes of microglia in the presence of amyloid pathology in 5xFAD mice.
Conclusions: PLCG2 variants confer divergent microglial phenotypic function in AD pathophysiology and defining these differences will be important in the development of microglia-directed therapeutics.
Discussants
Session Name
Session Type
FORUM
Date
Sun, 20.03.2022
Session Time
11:35 AM - 12:35 PM
Room
ONSITE PLENARY: 115-117
Lecture Time
11:35 AM - 12:35 PM