TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury

Abstract

Sequence variations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to an increased risk for neurodegenerative 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 wild-type 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 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., 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.

The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

“…MGnD microglia may also be protective and represent an initial response to neuronal injury. As we showed recently, TREM2 deficiency may lock microglia in a homeostatic state (Mazaheri et al, 2017) and block essential defense functions of microglia during disease progression. In summary, we demonstrate that the TREM2-APOE pathway induces a microglia phenotype switch from a homeostatic to neurodegenerative phenotype.…”

Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease

“…These observations suggest that ABI3 expressed on microglia in NC, AD, and NHD brains might positively regulate their motility and migration capacity via formation of podosomes, particularly when the activity of c-ABL tyrosine kinase is suppressed. In contrast, ABI3 mRNA expression is upregulated in TREM2-deficient microglia that exhibit a reduction in chemotaxis and migration (25).…”

The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism

“…It is known that myelinassociated lipids can trigger TREM2 signaling in vitro (Poliani et al, 2015;Wang et al, 2015) and Trem2 knockout mice are not capable of responding properly to myelin damage upon cuprizone-induction demyelination (Cantoni et al, 2015;Poliani et al, 2015). This is in line with a reduced sensing of myelinassociated lipids (Poliani et al, 2015;Wang et al, 2015) as well as a general defect of chemotaxis of Trem2-deficient microglia (Mazaheri et al, 2017). Our findings support the idea that microglial nodulelike structures are also formed during physiological aging and may represent a clearance mechanism of minor white matter insults.…”

“…Furthermore, loss of Trem2 or its signaling adaptor DNAX activation protein of 12 kDa (DAP12) has been shown to affect proliferation and survival of macrophages (Otero et al, 2012;Wu et al, 2015) and microglia in a CSF1 and sTrem2 concentration-dependent manner. Moreover, transcriptomic analyses revealed that microglia may be locked in a homeostatic stage in the absence of Trem2 (Mazaheri et al, 2017). Moreover, transcriptomic analyses revealed that microglia may be locked in a homeostatic stage in the absence of Trem2 (Mazaheri et al, 2017).…”