The Gain-of-Function TREM2-T96K Mutation Increases Risk for Alzheimer’s Disease by Impairing Microglial Function [scRNA-Seq]

The aim of this study is to characterize the underlying molecular mechanisms of the gain-of-function Trem2T96K mutation in Alzheimer’s disease (AD) pathogenesis by using the constitutive Trem2T96K knock-in mouse crossed to the 5xFAD mouse model of AD. By transcriptional single cell sorting, we comprehensively mapped all microglial populations in 8-month-old female 5xFAD;Trem2+/+, 5xFAD;Trem2T96K/+, and 5xFAD;Trem2T96K/T96K mice. Single-cell RNA-seq analysis revealed that Trem2T96K leads to concomitant suppression of the disease-associated microglia (DAM) gene signature and activation of homeostatic (HOM) genes and impairs the transition of HOM microglia into DAM in female 5xFAD mice. Collectively, these results suggest that Trem2T96K leads to reduced microglial immune activation in female 5xFAD mice. Transcriptional profiling of single cells from CD11b+CD45Low-to-Intermediate microglial populations of 8-month-old female Trem2+/+, Trem2T96K/+, 5xFAD;Trem2+/+, 5xFAD;Trem2T96K/+, and 5xFAD;Trem2T96K/T96K mice, generated from deep sequencing of tens of thousands of cells, sequenced on Illumina NextSeq 2000 sequencing platform.