Disease stage-dependent role of Trem2 in plaque-associated microglia clustering and neuritic dystrophy in an APP mouse model Sophia Bardehle1, Ilknur Icke2, Keith Tanis3, Sidney Hsieh1, Elaine K. O'Loughlin1, Gonzalo Zeballos1, Christopher Ware1, Veera Mahadomrongkul1, Jianhua Huang1, Gain Robinson4, Yuchuan Wang5, Tapan K. Nayal5, Michelle C. Potter1, Joel A. Klappenbach6, Matthew E. Kennedy1, Christian Mirescu1 1Merck &Co., Inc., Neuroscience Discovery, Boston; 2Merck &Co., Inc., Scientific Informatics, Boston; 3Merck &Co., Inc., Genetics & Pharmacogenomics, West Point; 4Merck &Co., Inc., Imaging, Boston; 5Merck &Co., Inc., Large molecule PET tracers, West Point; 6Merck &Co., Inc., Genetics & Pharmacogenomics, Boston
Alzheimer's disease (AD), the most common cause of dementia, is a complex neurodegenerative disease marked by amyloid-beta plaques and hyperphosphorylated tau tangles. Converging evidence from genome-wide association studies (GWAS) and transcriptomics highlight the importance of microglial genes as causal modulators of AD susceptibility. Particularly noteworthy are rare LoF variants in Trem2. We profiled the Abeta plaque niche by laser capture microdissection followed by RNAseq and report enrichment of Trem2 and several key pathway-implicated genes around Abeta plaques in transgenic TgCRND8 mice with overexpression of human APP(Swe/Ind). Using high-resolution confocal imaging, the Trem2 receptor is not only enriched within the plaque niche, but at the subcellular level appears highly localized to the microglia-plaque immune synapse. The cell and molecular mechanisms by which Trem2 mediates microglial responses to AD pathology and modulates neuritic dystrophy across disease course remain largely unknown. To investigate disease stage-dependent functions of Trem2 with regard to amyloid deposition, microglia barrier formation and impact on local neuritic dystrophy, we crossed TgCRND8 and Trem2KO mice. We characterized the impact of Trem2 ablation on the course of amyloid deposition and insoluble Abeta 40/42 accumulation, as well as by PET imaging changes of amyloid tracer [11C]PiB and TSPO tracer [11C]PBR28. RNASeq analysis of cortical CD11b+ cells isolated from 3 and 6 months old TgCRND8 mice showed age-related upregulation of reported disease-associated microglia (DAM) gene signatures in Trem2WT but not in Trem2KO cells, suggesting impaired polarization or altered distribution of microglia. We found that Trem2KO microglia fail to cluster around plaques via IHC imaging, indicating either chemotactic and/or proliferation defects. To further correlate microglia distribution and neuritic dystrophy on the single-plaque level, we developed a 3D multi-channel image analysis pipeline. This analysis platform confirmed impaired plaque-associated microglia clustering, with decreased microglia barrier width, increased plaque size, and extent of neuronal damage in TgCRND8 Trem2KO mice. In accordance with studies in other APP models, our data are consistent with the view that the Trem2 receptor is crucial to trigger microglia responses to Abeta pathology. Our study provides novel and confirming data on the key role of Trem2 in regulating microglial polarization, localization and the progression of Abeta pathology in mice. Ongoing efforts are aimed at understanding how pharmacological modulation of Trem2 activation can promote adaptive microgliosis and potentially modulate the progression of plaque-associated neuritic dystrophy.
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