Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer’s disease

Abstract

Background Disease-associated microglia (DAMs), that surround beta-amyloid plaques, represent a transcriptionally-distinct microglial profile in Alzheimer’s disease (AD). Activation of DAMs is dependent on triggering receptor expressed on myeloid cells 2 (TREM2) in mouse models and the AD TREM2-R47H risk variant reduces microglial activation and plaque association in human carriers. Interestingly, TREM2 has also been identified as a microglial lipid-sensor, and recent data indicates lipid droplet accumulation in aged microglia, that is in turn associated with a dysfunctional proinflammatory phenotype. However, whether lipid droplets (LDs) are present in human microglia in AD and how the R47H mutation affects this remains unknown. Methods To determine the impact of the TREM2 R47H mutation on human microglial function in vivo, we transplanted wild-type and isogenic TREM2-R47H iPSC-derived microglial progenitors into our recently developed chimeric Alzheimer mouse model. At 7 months of age scRNA-seq and histological analyses were performed. Results Here we report that the transcriptome of human wild-type TREM2 and isogenic TREM2-R47H DAM xenografted microglia (xMGs), isolated from chimeric AD mice, closely resembles that of human atherosclerotic foam cells. In addition, much like foam cells, plaque-bound xMGs are highly enriched in lipid droplets. Somewhat surprisingly and in contrast to a recent in vitro study, TREM2-R47H mutant xMGs exhibit an overall reduction in the accumulation of lipid droplets in vivo. Notably, TREM2-R47H xMGs also show overall reduced reactivity to plaques, including diminished plaque-proximity, reduced CD9 expression, and lower secretion of plaque-associated APOE. Conclusions Altogether, these results indicate lipid droplet accumulation occurs in human DAM xMGs in AD, but is reduced in TREM2-R47H DAM xMGs, as it occurs secondary to TREM2-mediated changes in plaque proximity and reactivity.

A cross-disease human microglial framework identifies disease-enriched subsets and tool compounds for microglial polarization

“…Label transfer offers the opportunity to extend our existing structure to external datasets, and our results suggest that both a human iPSC xenograft microglial model system 60 and an in vitro human iPSC microglial model system 62 recapitulate an impressive amount of the heterogeneity that we observed in tissue-derived live microglia, an encouraging sign for the field. We also recapitulate previously reported findings in these systems, such as an overrepresentation of a plaque and lipid-associated SPP1-high state in the in vivo 5XFAD model 61 . Similarly, the analysis of a GBM dataset 58 generated using a microwell-based scRNA-seq technology 68 highlights the role of cluster 11 microglia in that context, consistent with prior literature 64 .…”

Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia

“…3 d-e). Together, these observations indicate broad changes in microglia lipid metabolism in the App SAA KI mouse model, reminiscent of findings in human AD brains [ 72 ] and other AD mouse models [ 73 , 74 ].…”

Synapses, Microglia, and Lipids in Alzheimer’s Disease

“…Indeed, “lipid-droplet-accumulating microglia” (LDAM) accrue with age in humans and mice and exhibit defective phagocytic capability, overproduce reactive oxygen species, and secrete excess signalling cytokines such as TNFα, IL1β, and IL6 ( Marschallinger et al, 2020 ; cf., Figure 1 ). The accumulation of lipid droplets have also been noted in APP / PS1 chimeric mice xenografted with wild-type or R47H-TREM2 mutant iPSCs ( Claes et al, 2021 ). In the latter study, the R47H mutation resulted in reduced clustering of microglia at plaques but critically did not impair the formation of lipid droplets within individual cells.…”