Lee SH, Meilandt WJ, Xie L, Gandham VD, Ngu H, Barck KH, Rezzonico MG, Imperio J, Lalehzadeh G, Huntley MA, Stark KL, Foreman O, Carano RA, Friedman BA, Sheng M, Easton A, Bohlen CJ, Hansen DV. Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology. Neuron. 2021 Apr 21;109(8):1283-1301.e6. Epub 2021 Mar 5 PubMed.

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  1. David Hansen and colleagues present a comprehensive study in mouse models, examining the roles of microglia and Trem2 in the Aβ-tau axis of pathology of Alzheimer’s disease (AD). Their data adds to the growing evidence in mice, and humans, that loss of homeostatic microglia functions is central to the development of AD pathology. In particular, their study dissects, in mice, the precise contribution of Trem2 loss of function when both amyloid and tau pathologies are present, versus either of those pathologies in isolation.

    In our earlier studies (Condello et al., 2015), we found that microglia that envelop amyloid plaques act as a barrier that prevents outward plaque expansion, and their presence leads to a more compact plaque phenotype; areas not covered by microglia processes display less compact and outwardly radiating amyloid fibrils. The potential importance of this finding is the fact that axons near areas of the plaque not covered by microglia develop more dystrophies than those near areas covered by microglia.

    A subsequent study showed that Trem2 haplo-insufficiency in mice, and the TREM2 R47H variant in humans, was associated with a loss of microglia polarization toward plaques and a consequent change in plaque phenotype from a compact to a more diffuse one, which was also associated with an increase in the degree of axonal dystrophy and tau hyperphosphorylated neurites (Yuan et al., 2016).

    Our observations have since been confirmed in several Aβ mouse models using murine Trem2 knockouts (Wang et al., 2016; Meilandt et al., 2020), human TREM2 knock-ins (Leyns et al., 2019), and Trem2 overexpression (Lee et al., 2018), as well as a genetic microglial ablation model (Zhao et al., 2017). Questions remained, however, about the neuroprotective roles of microglia and Trem2. For example, there is some evidence of an age- or stage-dependent variation in Trem2-mediated neuroprotective functions (Jay et al., 2017; Leyns et al., 2017) and even potential deleterious roles of microglia in models of tauopathy without amyloidosis (Bemiller et al., 2017).

    In this interesting paper by the Hansen group, they systematically addressed some of these questions through single-cell RNA-seq, histology, biochemistry, and MRI in mutant mice. The authors conclude that Trem2 deletion in microglia exacerbates pathogenic tau accumulation and consequent neurodegeneration, but only in the presence of amyloid plaques. These data are complementary to findings in an Aβ mouse model injected with AD brain-derived tau (Leyns et al., 2019) and postmortem human AD samples (Yuan et al., 2016; Prokop et al., 2019), both of which show that TREM2 deficiency in microglia worsened axonal dystrophy and increased phosphorylated tau accumulation around plaques. Aside from Aβ pathology, the Hansen group report that modest transcriptional changes are observed in tauopathy-only mice, showing an incomplete “DAM” transcriptional conversion compared to wild-type mice; this is in agreement with prior work (Matarin et al, 2015; Friedman et al., 2018). They also show that deletion of one or two copies of Trem2 caused no significant changes in markers of tau pathology or neurodegeneration in tauopathy-only mice. This finding adds to a spectrum of results on Trem2 insufficiency in models of primary tauopathy, where loss of functional Trem2 has been shown to be detrimental or protective (Bemiller et al., 2017; Leyns et al., 2017: Sayed et al., 2018).

    Differences in how mice are engineered to express human MAPT (e.g., different gene promoter, specific tau isoform with or without familial mutation) may contribute to distinct pathological outcomes in the context of Trem2 insufficiency. Furthermore, mouse background may also play a role given that in two recent papers, different strains of mice appear vulnerable or resistant to Aβ pathology, exhibit differential regulation of AD-risk genes like Trem2, and can display partially overlapping DAM transcriptional profiles (Neuner et al., 2019; Yang et al., 2021).

    Mounting data suggest that other AD-risk genes/proteins modulate the expression of or bind to TREM2 such as MS4A (Deming et al., 2019) or APOE (Atagi et al., 2015; Yeh et al., 2016), respectively. Thus, it is possible that such genetic variants, or cellular senescence, affect microglial pathways that converge upon TREM2 to modulate its biological activity. Whatever the upstream cause, failed activation of protective transcriptional phenotypes and microglia barrier function appear to facilitate Aβ plaque-associated tau pathology, and possibly the rate of neurodegeneration and cognitive decline. The models and strategies provided in this new study by the Hansen lab could be of great utility for future mechanistic studies and investigation of therapeutic interventions aimed at microglia and Trem2.

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