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

Jan 15, 2021Proceedings of the National Academy of Sciences of the United States of America

Microglia responses to anti-human TREM2 vary with their prior activation in a mouse model of Alzheimer's disease

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Abstract

A single systemic injection of hT2AB activated microglia in 5XFAD transgenic mice with impaired TREM2 responses.

TREM2 engagement is linked to microglial responses to various brain injury stimuli.
Distinct activation trajectories of microglia were identified, including disease-associated and interferon-responsive types.
Cyc-M and IFN-R microglia were more prevalent in female 5XFAD mice, possibly due to increased amyloid β load.
hT2AB treatment replenished specific microglial populations in male 5XFAD mice but did not change overall representation.
Repeated administration of a murinized hT2AB version elevated chemokine levels associated with microglial expansion.

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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 thevariant, 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 () orscRNA-seq of microglia from-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-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-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-5XFAD mice. In-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-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. TREM2TREM2TREM2TREM2TREM2TREM2TREM2TREM2TREM2R47H CV R47H CV R47H CV R47H CV R47H

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

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