The Gain-of-Function TREM2-T96K Mutation Increases Risk for Alzheimer's Disease by Impairing Microglial Function

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. Gene expression analyses were performed on microglial cells isolated from male and female Trem2+/+ (WT), 5xFAD;Trem2+/+, 5xFAD;Trem2T96K/+, and 5xFAD;Trem2T96K/T96K mice at 8 months of age to analyze the impact of the Trem2T96K mutation on the transcriptome of microglia in the setting of neuroinflammation (i.e. in the 5xFAD brain). The results revealed that Trem2T96K reprogrammed microglial gene expression and downregulated signaling pathways related to microglial function, specifically, in female 5xFAD mice. Overall design: Microglia were isolated from brains of both male and female Trem2+/+, 5xFAD;Trem2+/+, 5xFAD;Trem2T96K/+, and 5xFAD;Trem2T96K/T96K mice at 8 months of age, using FACS sorting for CD11b and CD45. Libraries were prepared using the Nextera XT DNA Sample Prep Kit (Illumina) and sequenced on an Illumina NextSeq 2000 sequencing system. Reads were aligned to mouse genome mm9 using the STAR aligner.