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Mazaheri, Fargol; Snaidero, Nicolas; Kleinberger, Gernot; Madore, Charlotte; Daria, Anna; Werner, Georg; Krasemann, Susanne; Capell, Anja; Trümbach, Dietrich; Wurst, Wolfgang; Brunner, Bettina; Bultmann, Sebastian; Tahirovic, Sabina; Kerschensteiner, Martin; Misgeld, Thomas; Butovsky, Oleg and Haass, Christian ORCID logoORCID: https://orcid.org/0000-0002-4869-1627 (2017): TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. In: Embo Reports, Vol. 18, No. 7: pp. 1186-1198

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Sequence variations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to an increased risk for neurode-generative disorders such as Alzheimer's disease and frontotemporal lobar degeneration. In the brain, TREM2 is predominantly expressed in microglia. Several disease-associated TREM2 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 TREM2 loss of function on the microglia transcriptome. Among the differentially expressed messenger RNAs in wildtype and Trem2(-/-) microglia, gene clusters are identified which represent gene functions in chemotaxis, migration and mobility. Functional analyses confirm that loss of TREM2 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 TREM2 reduces the distance migrated by microglia. Moreover, migration towards defined chemo-attractants is reduced upon ablation of TREM2 and can be rescued by TREM2 re-expression. In vivo, microglia lacking TREM2 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 TREM2 is consistent with a stable expression profile of genes characterizing the homoeostatic signature of microglia.

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