Basic Science and Pathogenesis

Alzheimer's Disease (AD) risk variants APOE4 and TREM2-R47H are known to impact glial cell functions and transcriptional profiles. TREM2-mediated oligodendrocyte-microglial crosstalk has not been revealed in previous research studies. Here, we present novel findings suggesting a TREM2-dependent mediation of oligodendrocyte transcriptional profiles.

We investigated cell-type specific transcriptional changes associated with humanized APOE4 and TREM2-R47H genotypes in P301S+ mice versus background controls via single-nuclei RNA-sequencing of the frontal cortex. We investigated cell type subcluster abundance in association with genotype, sex and tau-positivity. We classified subclusters through differentially expressed gene network modules and gene set enrichment analysis. We compared our findings in mice to a human cohort. The mouse cohort consisted of 52 humanized APOExTREM2 mice, with six-to-eight mice per genotype-tau group, evenly split on sex. The human cohort consisted of 55 AD and control humans: APOE4-carrier TREM2-R47H (E4-R47H) (n = 18), nonE4-R47H (nonE4-R47H) (n = 6), APOE4-carrier TREM2-common variant (E4-CV) (n = 16), nonE4-CV (n = 6).

We found that APOE-TREM2 status had sex- and tau-independent TREM2-R47H-specific effects, and APOE4-R47H synergistic effects on cell abundance in oligodendrocytes, oligodendrocyte progenitor cells (OPCs), and a subgroup of inhibitory neurons. Specifically, we identified OPC and oligodendrocyte subclusters that strongly associate with TREM2-R47H in a tau-independent manner, further exacerbated by APOE genotype. Of note, the human cohort also showed a strong synergistic effect of APOE4 and TREM2-R47H on an oligodendrocyte subcluster that may be related to the TREM2-R47H-dependent oligodendrocyte subclusters identified in the mice. This finding of TREM2-specific effects on oligodendrocyte transcriptional states in both mice and humans suggests possible TREM2-mediated microglia-oligodendrocyte crosstalk, or the presence of TREM2-oligodendrocyte cell-ligand interactions that merits further investigation.

In summary, this study suggests possible synergistic effects of APOE4-carrier and TREM2-R47H-carrier status on OPC, oligodendrocyte, and inhibitory neuron abundance and transcriptional profiles. Specifically, OPCs and oligodendrocytes show a strong association with TREM2-R47H that is exacerbated by APOE genotype, a finding that is reflected in the human cohort. Hence, further classification of differences between joint APOE-TREM2 genotypes will improve our understanding of glial cell alterations in AD, and could lead to novel cell type-specific therapeutic interventions for AD and other AD-related dementia if broadly applied.