Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology
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PROVIDER: PRJNA750778 | ENA |
REPOSITORIES: ENA
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Project 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.
2021-07-30 | GSE181135 | GEO
Project 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.
2021-10-08 | GSE185510 | GEO
Project description:Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology [14 months]
| PRJNA769396 | ENA
Project description:Polygenic risk factors influence onset and progression of neurodegenerative diseases, but are difficult to be functionally explored in isolation. Single nucleotide polymorphisms (SNPs) in TMEM106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN mutation carriers. Currently, it is not clear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss-of-function of TMEM106B is responsible for the increased disease risk of patients with PGRN haploinsufficiency. We therefore compared behavioral abnormalities, gene expression patterns, lysosomal activity and TDP-43 pathology in single and double knockout animals. Grn–/–/Tmem106b–/– mice showed a strongly reduced life span and massive motor deficits. Gene expression analysis revealed an upregulation of molecular signatures characteristic for disease associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as a pronounced accumulation of ubiquitinated proteins and wide spread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn–/– knockouts only occasionally showed TDP-43 pathology, the double knockout mice exhibit robust deposition of phosphorylated TDP-43. Thus, a loss-of-function of TMEM106B may enhance the risk for GRN-associated FTD by reduced protein turnover in the lysosomal/autophagic system.
2020-07-25 | GSE155066 | GEO
Project description:Polygenic risk factors influence onset and progression of neurodegenerative diseases, but are difficult to be functionally explored in isolation. Single nucleotide polymorphisms (SNPs) in TMEM106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN mutation carriers. Currently, it is not clear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss-of-function of TMEM106B is responsible for the increased disease risk of patients with PGRN haploinsufficiency. We therefore compared behavioral abnormalities, gene expression patterns, lysosomal activity and TDP-43 pathology in single and double knockout animals. Grn–/–/Tmem106b–/– mice showed a strongly reduced life span and massive motor deficits. Gene expression analysis revealed an upregulation of molecular signatures characteristic for disease associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as a pronounced accumulation of ubiquitinated proteins and wide spread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn–/– knockouts only occasionally showed TDP-43 pathology, the double knockout mice exhibit robust deposition of phosphorylated TDP-43. Thus, a loss-of-function of TMEM106B may enhance the risk for GRN-associated FTD by reduced protein turnover in the lysosomal/autophagic system.
2020-07-25 | GSE155065 | GEO
Project description:Patients with frontotemporal dementia (FTD) resulting from granulin (GRN) haploinsufficiency have reduced levels of progranulin and exhibit dysregulation in inflammatory and lysosomal networks. Microglia produce high levels of progranulin, and reduction of progranulin in microglia alone is sufficient to recapitulate inflammation, lysosomal dysfunction, and hyperproliferation in a cell-autonomous manner. Therefore, targeting microglial dysfunction caused by progranulin insufficiency represents a potential therapeutic strategy to manage neurodegeneration in FTD. Limitations of current progranulin-enhancing strategies necessitate the discovery of new targets.To identify compounds that can reverse microglial defects in Grn-deficient mouse microglia, we performed a compound screen coupled with high throughput sequencing to assess key transcriptional changes in inflammatory and lysosomal pathways. Positive hits from this initial screen were then further narrowed down based on their ability to rescue cathepsin activity, a critical biochemical readout of lysosomal capacity. The screen identified nor-binaltorphimine dihydrochloride (nor-BNI) and dibutyryl-cAMP, sodium salt (DB-cAMP) as two phenotypic modulators of progranulin deficiency. In addition, nor-BNI and DB-cAMP also rescued cell cycle abnormalities in progranulin-deficient cells. These data highlight the potential of a transcription-based platform for drug screening, and advance two novel lead compounds for FTD.
2020-08-02 | GSE143144 | GEO
Project description:TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer’s Disease (AD) risk. In mouse models of amyloid b (Ab) accumulation, defective TREM2 function affects microglial response to Ab plaques exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior and tempered glial inflammatory response. We further showed that a variant of AL002c has been given safely in a first-in-human phase I clinical trial and engages TREM2 based on CSF biomarkers. We conclude that AL002c is a promising candidate for AD therapy.
2020-05-13 | GSE150358 | GEO
Project description:Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. 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 led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody-treated PGRN-deficient microglia derived from human-induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light-chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2-dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection.
| S-EPMC8844989 | biostudies-literature
Project description:Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin deficient mice [neuropathology panel]
| PRJNA648369 | ENA
Project description:Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin deficient mice [neuroinflammation panel]
| PRJNA648370 | ENA