In a Commentary article published in MolNeuro, NimanshaJ and Jason D. Ulrich discuss a recent study that highlights the role of the microglial endolysosomal system and TREM2 in the spread of tau pathology.
]. In contrast to how removal of microglia inhibited the spread of tau pathology, TREM2 KO mice exhibited exacerbated spread of tau into the dentate gyrus region of the hippocampus, which also corresponded with synaptic loss and cognitive impairment. Using a three-chamber cell culture system, the authors demonstrated that microglia were necessary intermediaries in the spread of tau between non-adjoining neurons.
How TREM2 influences microglial extrusion of tau in exosomes remains to be resolved. Microglial or macrophage uptake of tau does not appear to depend on TREM2 expression in vitro. However, TREM2 appears to regulate the intracellular itinerary within the endolysosomal system. Zhu, Liu et al. found that 4 hours after oligomeric tau administration, tau in WT microglia robustly co-localized with LAMP1+ lysosomes.
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