Examining how the TREM2 R47H mutation effects microglial lipid content and the interactions between human microglia and AD pathology within the brain

Summary

Alzheimer's disease is the most common type of dementia that causes problems with memory, thinking and behavior, and so far we don’t understand this disease well enough to find a cure to help these patients. In our proposal, we want to increase our understanding of this disease by studying microglia, the resident immune cells of the brain, and a gene called TREM2 which when mutated can significantly increase the risk of developing Alzheimer’s disease. Our recent studies show that when we transplant healthy human stem cell-derived microglia carrying a normal version of TREM2 into the brain of Alzheimer mice that develop amyloid plaques (a main characteristic of this disease), human microglia near the plaques show similarities to peripheral ‘foam cells’, which are immune cells filled with lipids and linked with another disease called “atherosclerosis”. As TREM2 is a lipid-sensor expressed by microglia, we now want to study the lipid content and the reaction of human microglia that carry the TREM2 R47H mutation to amyloid plaques in this specialized mouse model, to greatly improve our understanding of how this mutation can increase Alzheimer’s risk, which will in turn allow scientists to find treatments that increase the functionality of microglia to protect our brain from the damage caused by these amyloid plaques.

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Lipid droplets (red, PLIN2) accumulate in GFP+ human microglia (green) surrounding amyloid plaques (blue, amylo-glo) in the hippocampus of chimeric Alzheimer mice. Lipid droplet accumulation in microglia has recently been shown to impair microglial functions. Therefore, improving our understanding of lipid composition in both wild-type and TREM2 mutant microglia might offer exciting new avenues for future therapeutics.

Project Details

The primary goal of this proposal is to examine the impact of an Alzheimer’s disease (AD)-associated mutation in the gene TREM2 on the function, transcriptome, and lipidome of human microglia. Specifically, we will utilize our recently developed chimeric mouse model of AD to examine the interactions between AD pathology and human microglia and how TREM2-R47H mutations, that increase AD risk by 3-fold, alter these dynamic interactions. Importantly, our humanized AD mouse model develops amyloid plaques, the primary hallmark pathology of AD. Our model therefore provides a unique opportunity to genetically manipulate and examine human plaque-surrounding disease-associated microglia (DAMs). Using this model we will address multiple important questions, namely “What is the effect of the R47H mutation on the transcriptome of human microglia in vivo”? and “How do R47H mutant human microglia impact AD pathology in vivo”?. Interestingly, TREM2 is known as a lipid-sensing receptor. Therefore, we wonder “If the R47H mutation reduces the ability of microglia to respond to and/or metabolize lipids?”. Moreover, a recent study demonstrated that aged microglia accumulate lipid droplets, and excessive accumulation of lipids within peripheral macrophages induces foam cell formation. As the R47H mutation is a risk factor for AD in aged individuals, we wonder “If the R47H mutation alters lipid (droplet) composition of human microglia in vivo?”. Finally, foam cells are known to increase secretion of APOE and DAMs have also been shown to secrete APOE around plaques. Therefore, we will determine “whether the association of APOE with amyloid plaques will be reduced in AD brains transplanted with R47H mutant vs. wild-type human microglia?”. To address each of these pressing questions, we propose to perform a transcriptomic and lipidomic analysis of isogenic wild-type and TREM2 R47H xMGs transplanted into chimeric AD and wild-type mice. Coupled with immunohistochemical and quantitative confocal analysis of human microglia and AD pathology, our proposed studies will significantly increase our understanding of human microglial lipid metabolism, which could open up new therapeutic avenues in AD, and determine how the R47H TREM2 risk mutation affects this and other aspects of AD pathogenesis.