| Experiment Id | GSE185510 | Name | Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology [14 months] |
| Experiment Type | transcription profiling by array | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2022-03-02 |
| description | GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model. In this study we analyzed gene expression in total RNA isolated from whole brain of adult mice. We compared the expression profile of Trem2 knockout mice , Grn knockout mice, and Grn/Trem2 double knockout mice (for each genotype n=3 female, n=3 male, 14 month) to wild type mice (n=3 female, n=3 female, 14 months). Please note that the normalized data for the GSM5617157 - GSM5617168 samples have been updated on Oct 15, 2021. |
