Frontiers Journal of Neurology & Neuroscience

The Interplay Of TREM2 And APOE – Effects On Brain Transcriptome And Phenotype Of AD Model Mice

Abstract

Apolipoprotein E4 (APOE4) is the major genetic risk factor for Late Onset AD (LOAD). Recently, Genome-Wide Association Studies (GWAS) on very large populations identified disease specific variants of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as potential risk factors for AD. TREM2 expressed in microglia promotes cell survival, proliferation, and phagocytosis, making it essential for their immune function. Studies using protein binding assays suggest that APOE is a ligand that can bind TREM2, potentially in an isoform specific manner. TREM2 is not unique in providing defense immune mechanisms, particularly in brain, and while TREM2 variants have a minor impact on the overall incidence of LOAD, genetically engineered AD model mice expressing human APOE isoforms and lack TREM2 are a complex animal model of AD that helps in understanding the pathogenesis of LOAD. We designed a study to test the hypothesis that TREM2 deficiency will differentially modulate brain transcriptome and therefore the phenotype of AD model mice expressing human APOE3 or APOE4. In APP/PS1/APOE3 or APP/PS1/APOE4 mice the evaluation of amyloid deposition, plaque associated APOE, microglia barrier around the plaques, differential gene expression and transcriptomic profiles, allow us to conclude that:

      Trem2 deficiency does not impact total amyloid plaque deposition in either APP/PS1/APOE3 or APOE4 expressing mice (6.5 mo);

      While plaque associated APOE is significantly higher in APP/PS1/APOE4 mice compared to APP/PS1/APOE3, global deletion of Trem2 decreases plaque associated APOE4 in APP/PS1/APOE4, but has no significant effect in APP/PS1/APOE3 mice;

      Trem2 deficiency significantly diminishes the number of plaque associated microglia in both genotypes, but more in APP/PS1/APOE4 mice, and

      Brain transcriptome is significantly more impacted by Trem2 deficiency in APOE4 expressing mice.

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