Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA105315 | ENA |
REPOSITORIES: ENA
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Project description:The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous TREM2 variants subtly impair microglia, facilitating manifestation of Alzheimer’s Disease in the elderly. Homozygous inactivating mutations of TREM2 or DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia with leukoencephalopathy, myelin loss and gliosis. Here we investigated the impact of DAP12 deficiency in microglia and collateral damage to other brain cells by single-nucleus RNA-seq in NHD patients and DAP12 loss-of-function (KΔ75) mice. KΔ75 mice showed signatures of impaired microglia activation that reverberated in mild dysfunction of other brain cells. Paradoxically, NHD microglia were activated and associated with astrocytosis, hypoxia, and neuronal loss signatures. We envision that KΔ75 signatures recapitulate an early NHD stage in which DAP12-deficient microglia fail to clear toxic products generated during brain development and homeostasis. Conversely, NHD signatures reflect a late disease stage in which accumulated toxic products cause a widespread tissue damage that elicits TREM2-DAP12-independent microgliosis, astrogliosis, hypoxia, and neuronal death. This TREM2-DAP12-independent microglia activation in NHD has bearing on potential microglia-based therapies.
2022-12-31 | GSE190012 | GEO
Project description:The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous TREM2 variants subtly impair microglia, facilitating manifestation of Alzheimer’s Disease in the elderly. Homozygous inactivating mutations of TREM2 or DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia with leukoencephalopathy, myelin loss and gliosis. Here we investigated the impact of DAP12 deficiency in microglia and collateral damage to other brain cells by single-nucleus RNA-seq in NHD patients and DAP12 loss-of-function (KΔ75) mice. KΔ75 mice showed signatures of impaired microglia activation that reverberated in mild dysfunction of other brain cells. Paradoxically, NHD microglia were activated and associated with astrocytosis, hypoxia, and neuronal loss signatures. We envision that KΔ75 signatures recapitulate an early NHD stage in which DAP12-deficient microglia fail to clear toxic products generated during brain development and homeostasis. Conversely, NHD signatures reflect a late disease stage in which accumulated toxic products cause a widespread tissue damage that elicits TREM2-DAP12-independent microgliosis, astrogliosis, hypoxia, and neuronal death. This TREM2-DAP12-independent microglia activation in NHD has bearing on potential microglia-based therapies.
2022-12-31 | GSE190013 | GEO
Project description:Engrams are considered to be substrates for memory storage, and the functional dysregulation of the engrams leads to cognition impairment.However, the cellular basis for these maladaptive changes lead to the forgetting of memories remains unclear. Here we found that the expression of autophagy protein 7 (Atg7) mRNA was dramatically upregulated in aged DG engrams, and led to the forgetting of contextual fear memory and the activation of surrounding microglia.To determine mechanism by which autophagy in DG engrams activates the surrounding microglia, mice were co-injected AAV-RAM-Cre either with AAV-Dio-Atg7-Flag or AAV-Dio- EYFP in dorsal dentate gyrus to overexpress ATG7 in the DG memory engrams. Microglia were separated using magnetic-activated cell sorting and subjected to RNA-Seq in dorsal hippocampus .Bioinformatics analysis shown overexpression of Atg7 in dorsal DG memory engrams caused an increase in the expression of Tlr2 in the surrounding microglia.Depletion of Toll-like receptor 2/4 (TLR2/4) in DG microglia prohibited excessive microglial activation and synapse elimination induced by the overexpression of ATG7 in DG engrams, and thus prevented forgetting. Furthermore, the expression of Rac1, a Rho-GTPases which regulates active forgetting in both fly and mice, was upregulated in aged engrams. Optogentic activation of Rac1 in DG engrams promoted the autophagy of the engrams, the activation of microglia, and the forgetting of fear memory. Invention of the Atg7 expression and microglia activation attenuated forgetting induced by activation of Rac1 in DG engrams. Together, our findings revealed autophagy-dependent synapse elimination of DG engrams by microglia as a novel forgetting mechanism.
2021-08-24 | GSE169019 | GEO
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