AD-linked R47H-TREM2mutation induces disease-enhancing proinflammatory microglial states in mice and humans

Abstract

The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.

Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

“…Very recent studies have shown that tau protein (the other key player in the progression of AD) interacts with the intracellular polyglutamine binding protein 1 (PQBP1), and thereby, it activates pro-inflammatory genes that induce inflammation [60]. In a mouse model of AD, the R47H-TREM2 mutation induced NDD by robustly increasing pro-inflammatory cytokines via hyperactivation of AKT signalization [61].…”

TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation

“…The most characterised variant of TREM2 (p.R47H) shows defects in ligand binding [6,37,38,97], which impacts the ability of TREM2 to recognise damage, and induce microglial changes, resulting in a dampened response to pathological insults such as Aβ deposition. As TREM2 elicits its functional effect via activation of PLCγ2, it is not surprising that KO of PLCγ2 produces similar phenotypes and, indeed, PLCG2 KO iPSC microglia and macrophages exhibit reduced signalling, phagocytic deficits, and reduction in lipid metabolism, which are also observed in TREM2 KO iPSC lines [34].…”

“…Studies carried out on IPSCderived microglia-like cells [34] TREM2 p.R47H Impaired myeloid cell response to plaque in vivo and reduced proliferation [37], increased expression of pro-inflammatory cytokines [38], reduced cell adhesion and altered surface levels observed in iPSC-derived macrophages [39] Not clear Shown by [40] to increase apraxia, psychiatric and parkinsonian symptoms when compared to non-carriers, but no differences in clinical phenotype observed by [41] In non-symptomatic carriers, elderly individuals show poor cognitive function [42]). There seems to be too few studies with carriers vs non carriers to draw clear conclusions about the contribution of this variant to disease.…”

“…Alternative strategies could act on other enzymes in the TREM2/PLCγ2 signalling cascade. For instance, it has been suggested that p.R47H leads to hyperactivation of Akt downstream of Trem2 [38], therefore, Akt inhibitors could be considered as a potential approach to modulate disease-enhancing microglia states. However, as the main mediator of PI3K signalling, Akt is a central effector downstream of several signal transduction pathways, and it is involved in numerous cellular responses, such as protein synthesis, cell proliferation, cell motility, metabolism, survival, apoptosis, cell growth and cytokine production.…”

Antiviral Immune Response in Alzheimer’s Disease: Connecting the Dots

“…Therefore, a prototypical antiviral immune response is manifested in both pre-clinic models and clinic AD cases. Interestingly, AD patients with rare TREM2 R47H variant, an AD risk factor, have increased presentation of proinflammatory microglia subsets including those enriched with IFN response (Sayed et al, 2020).…”