TREM 2 deficiency impairs chemotaxis and microglial responses to neuronal injury

Sequence variations in the triggering receptor expressed on myeloid cells 2 ( TREM 2) have been linked to an increased risk for neurodegenerative disorders such as Alzheimer's disease and frontotemporal lobar degeneration. In the brain, TREM 2 is predominantly expressed in microglia. Several disease‐associated TREM 2 variants result in a loss of function by reducing microglial phagocytosis, impairing lipid sensing, preventing binding of lipoproteins and affecting shielding of amyloid plaques. We here investigate the consequences of TREM 2 loss of function on the microglia transcriptome. Among the differentially expressed messenger RNA s in wild‐type and Trem2 −/− microglia, gene clusters are identified which represent gene functions in chemotaxis, migration and mobility. Functional analyses confirm that loss of TREM 2 impairs appropriate microglial responses to injury and signals that normally evoke chemotaxis on multiple levels. In an ex vivo organotypic brain slice assay, absence of TREM 2 reduces the distance migrated by microglia. Moreover, migration towards defined chemo‐attractants is reduced upon ablation of TREM 2 and can be rescued by TREM 2 re‐expression. In vivo , microglia lacking TREM 2 migrate less towards injected apoptotic neurons, and outgrowth of microglial processes towards sites of laser‐induced focal CNS damage in the somatosensory cortex is slowed. The apparent lack of chemotactic stimulation upon depletion of TREM 2 is consistent with a stable expression profile of genes characterizing the homoeostatic signature of microglia. image TREM 2 sequence variations are linked to neurodegenerative disorders. Transcriptomic and functional studies show that TREM 2‐deficient microglia display a homeostatic mRNA signature and are impaired in chemotaxis and their response to neuronal injury. TREM2 deficiency in microglia affects expression profiles of gene clusters involved in chemotaxis. TREM2 deficiency impairs migration, chemotaxis and process outgrowth. TREM2‐deficient microglia display a homeostatic mRNA signature.