Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer’s disease (AD) risk is associated with the TREM2R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant (TREM2CV) or TREM2R47H. scRNA-seq of microglia from TREM2CV-5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types. All of these were underrepresented in TREM2R47H-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories. Moreover, Cyc-M and IFN-R microglia were more abundant in female than male TREM2CV-5XFAD mice, likely due to greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished Cyc-M, IFN-R, and MHC-II pools in TREM2R47H-5XFAD mice. In TREM2CV-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which these trajectories had already reached maximum capacity. Moreover, hT2AB induced shifts in gene expression patterns in all microglial pools without affecting representation. Repeated treatment with a murinized hT2AB version over 10 d increased chemokines brain content in TREM2R47H-5XFAD mice, consistent with microglia expansion. Thus, the impact of hT2AB on microglia is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation.

Disrupted microglial iron homeostasis in progressive multiple sclerosis

“…We first used published mouse data sets to determine the function of each cluster. Transcriptional signatures have been described for various microglia subclusters in murine models of disease, including neurodegenerative or disease-associated microglia (DAM), interferon-responsive (IFN-R), and antigen presenting (MHC-II high, MHCII+) related populations 17 . In contrast to murine models, these profiles did not discriminate as well between microglia from healthy and diseased patients.…”

Selection and structural characterization of anti-TREM2 scFvs that reduce levels of shed ectodomain

“…Because of the potential therapeutic impact of targeting TREM2, we decided to generate single-chain variable antibody fragments (scFvs) against the human TREM2 ectodomain with which to study TREM2 structure and function. Agonist antibodies have already been reported in recently published work (Ellwanger et al, 2021;Fassler et al, 2021;Ibach et al, 2021;Price et al, 2020;Schlepckow et al, 2020;Wang et al, 2020). The group of Schlepckow have shown that a full-length antibody specific to mouse TREM2 can decrease shedding and activate TREM2 signaling in vitro, and also lead to a significant reduction in amyloid plaques in 6-month-old amyloid-beta precursor protein knockin mice (Schlepckow et al, 2020).…”

Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease

“…TREM2 manipulation, either through genetic deletion or antibody-dependent activation, may have different effects on pathology in various amyloid-and tau-expressing AD mouse models [152][153][154][155][156]. Soluble forms of TREM2 also appear to modulate AD pathology through direct action on microglial phenotypes [157,158].…”

“…Specific microglial receptors, such as TREM2, provide an initial signal for DAM/MGnD activation by binding to ApoE [51,52,56]. Along these lines, recent studies have shown that humanized antibodies targeting TREM2 promote microglia activation, reduce pathology, correct cognitive deficits and dictate microglial responses even in AD mouse models carrying TREM2 variants [153,154,[226][227][228]. This is particularly important, as some TREM2 variants, such as TREM2-R47H [126], are considered loss-of-function mutations and are associated with worsened pathology in AD mouse models [62].…”