Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease

Nature Medicine 2020

Zhou, Yingyue and Song, Wilbur M. and Andhey, Prabhakar S. and Swain, Amanda and Levy, Tyler and Miller, Kelly R. and Poliani, Pietro L. and Cominelli, Manuela and Grover, Shikha and Gilfillan, Susan and Cella, Marina and Ulland, Tyler K. and Zaitsev, Konstantin and Miyashita, Akinori and Ikeuchi, Takeshi and Sainouchi, Makoto and Kakita, Akiyoshi and Bennett, David A. and Schneider, Julie A. and Nichols, Michael R. and Beausoleil, Sean A. and Ulrich, Jason D. and Holtzman, David M. and Artyomov, Maxim N. and Colonna, Marco

Abstract

Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single-cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single-cell microglia transcriptomes. We discovered microglial co-expression network modules associated with age, sex, and APOE-ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single-cell transcriptomes revealed significant overlap between age-associated module genes and both pro-inflammatory and disease-associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta-analyses with published bulk and single-cell microglial datasets further supported our findings. Thus, these data represent a well-characterized human microglial transcriptome resource and highlight age, sex, and APOE-related microglial immunometabolism perturbations with potential relevance in neurodegeneration.

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