TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration

Abstract

Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, in the central nervous system, is exclusively expressed on microglia. TREM2 variants have been linked to increased risk for neurodegenerative diseases, but the functional effects of microglial TREM2 remain largely unknown. To this end, we investigated TAR-DNA binding protein 43 kDa (TDP-43)-related neurodegenerative disease via viral-mediated expression of human TDP-43 protein (hTDP-43) in mice or inducible expression of hTDP43 with defective nuclear localization signals in transgenic mice. We found that TREM2 deficiency impaired microglia phagocytic clearance of pathological TDP-43, and enhanced neuronal damage and motor function impairments. Mass cytometry analysis revealed that hTDP-43 induced a TREM2-dependent subpopulation of microglia with high CD11c expression and higher phagocytic ability. Using mass spectrometry, we further demonstrated an interaction between TDP-43 and TREM2, in vitro and in vivo, in hTDP-43-expressing transgenic mouse brains. We computationally identified the region within hTDP-43 that interacts with TREM2 and observed the potential interaction in ALS patient tissues. Our data reveal the novel interaction between TREM2 and TDP-43, highlighting that TDP-43 is a potential ligand for microglial TREM2 and the interaction mediates neuroprotection of microglial TREM2 in TDP-43-related neurodegeneration.

A developmental atlas of the mouse brain by single-cell mass cytometry

“…Performing confocal immunofluorescence microscopy to observe the complete engulfment of neuronal and glial cargoes would provide further evidence that we are observing bona fide phagocytic events. If these putative phagocytic events are corroborated, future studies could provide a more detailed view of microglial subtypes and their phagocytic behavior by employing a hybrid antibody panel including additional markers to define microglial subpopulations 39,38,130,47,151,[43][44][45] , as well as markers of phagocytic activity and cargoes. With additional validation and characterization, this approach to quantify phagocytic cargoes could be extended beyond microglia to macrophages and "non-professional" phagocytes like neural crest cells 152 .…”

“…The antibody-based measurements from mass cytometry can directly read out functional biomolecules, unlike mRNA transcripts that do not necessarily correlate with protein abundancea disconnect most pronounced during dynamic cell transitions 28,29 like those occurring in early brain development. Mass cytometry was previously employed to investigate glioma [30][31][32][33][34][35][36][37] , microglia [38][39][40][41][42][43][44][45] , and dorsal root ganglia 46 , but this approach has not yet been applied to study neural cell types in the brain, except for one limited analysis with seven neural-specific markers in a study of obesity-inhibited adult neurogenesis 47 .…”

“…7a). Microglia were identified as CD45 mid CD11b high cells, but our ability to further specify microglial subtypes was restricted by our antibody panel including only four microglia-specific markers, as opposed to the microglia-focused panels used in previous mass cytometry studies 39,38,130,40,131,132,42,45 . However, while lacking in microgliasubtype specificity, our antibody panel enables detection and quantification of putative phagocytic cargoes, allowing us to divide microglia into two functional subtypes: "unladen" without cargo, and "cargo-laden" containing neuronal or glial markers (Fig.…”

Attack of the Clones: Microglia in Health and Disease

“…Instead of naming microglia as the major contributors to chronic neuroinflammation, several studies have shown that microglia surrounding the Aβ plaques form a compact physical barrier around them to limit further local neuronal damage (Condello et al, 2015;Yuan et al, 2016;Spangenberg et al, 2019). Moreover, microglial TREM2-mediated clearance of protein aggregates of human TAR-DNA binding protein 43 kDa (TDP-43) was neuroprotective in mouse models for the motor neuron degenerative disease ALS (Spiller et al, 2018;Xie et al, 2021). Taken together, microglial subpopulations near lesions or plaques can potentially have both beneficial and detrimental effects in chronic neurodegeneration.…”

What Is the Role of Microglial Metabolism in Inflammation and Neurodegeneration?

“…122 Furthermore, TREM2 binds multiple ligands relevant to neurodegeneration, including mutant TAR-DNA-binding protein of 43 kDa, suggesting a neuroprotective function in disorders such as motor neuron disease. 123…”