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Rescuing over-activated microglia by acetaminophen treatment restores cognitive performance in the Dp(16) mouse model of Down syndrome.

ABSTRACT: Microglia are the resident immune cells of the brain and have been implicated in mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by the presence of a supernumerary chromosome 21, which contains genes essential for the function of the immune system. Here, we investigated the presence of microglial alterations and their implication for cognitive impairment in the Dp(16) mouse model of DS. In the hippocampus of Dp(16) mice and individuals with DS, we found microglial morphology indicative of an activated state. Accordingly, we found an electrophysiological profile typical of activated microglia, increased levels of pro-inflammatory cytokines, and altered interferon signaling in Dp(16) mice. In addition, DS mice showed decreased neuronal spine density and neuronal activity, as well as cognitive behavioral deficits. Remarkably, depletion of defective microglia by PLX3397 treatment or rescue of the microglia activated state by the commonly used anti-inflammatory drug acetaminophen rescued the neuronal deficits and cognitive impairment in Dp(16) mice. Our data suggest an involvement of microglia in the cognitive impairment of DS animals and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137939 | GEO | 2020/09/22

REPOSITORIES: GEO

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Rescuing over-activated microglia by acetaminophen treatment restores cognitive performance in the Dp(16) mouse model of Down Syndrome.

Project description:Microglia are the resident immune cells of the brain and have been implicated in mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by the presence of a supernumerary chromosome 21, which contains genes essential for the function of the immune system. Here, we investigated the presence of microglial alterations and their implication for cognitive impairment in the Dp(16) mouse model of DS. In the hippocampus of Dp(16) mice and individuals with DS, we found microglial morphology indicative of an activated state. Accordingly, we found increased levels of pro-inflammatory cytokines and altered interferon signaling in Dp(16) mice. In addition, Dp(16) mice showed decreased dendritic spine density and cognitive deficits. Remarkably, depletion of defective microglia by PLX3397 treatment or rescue of the microglia activated state by the commonly used anti-inflammatory drug acetaminophen fully rescued dendritic-spine density and cognitive deficits in Dp(16) mice. Our data suggest an involvement of microglia in the cognitive impairment of DS animals and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.

2020-09-22 | PXD015113 | Pride

Rescuing over-activated microglia by acetaminophen treatment restores cognitive performance in the Dp(16) mouse model of Down Syndrome.

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Noncanonical Il-1β maturation in microglia impairs cognition in chronic kidney disease via neuronal IL1R signaling

Project description:While cognitive impairment is common in peripheral diseases such as chronic kidney disease (CKD), mechanistic insights and effective therapies are lacking. Here, we show that microglial potassium (K+) dyshomeostasis induces noncanonical IL-1β maturation and neuronal dysfunction via IL-1R signaling in CKD. Despite inflammasome activation in the brain, microglial caspase-1 deficiency does not improve inflammation and cognition in CKD mice. Noncanonical IL-1β maturation in microglia is mediated by the cathepsin C–caspase-8 pathway. Restoring K+ homeostasis in microglia or genetically inhibiting neuronal IL-1R1 signaling abolishes CKD-induced cognitive impairment. Microglial K+ dyshomeostasis and noncanonical microglial IL-1β maturation may therefore be druggable targets in some forms of cognitive impairment. These insights identify a new intercellular microglia–neuron crosstalk and identify potential therapeutic targets to combat inflammasome-induced neuronal dysfunction.

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SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1beta

Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1Î² selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1Î² transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1Î². Consistent with our findings in mice, selective hypomethylation of IL-1Î² at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia

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Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [snRNA-Seq]

Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.

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Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [bulk RNA-Seq]

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Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience II

Project description:Here we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of cGAS in tauopathy mice diminished microglial IFN-I response, preserved synapse integrity and plasticity, and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation enhanced, while activation of IFN-I downregulated, neuronal MEF2C expression network linked with cognitive resilience in AD.

2023-04-26 | GSE226381 | GEO

SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1beta

Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1β selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1β. Consistent with our findings in mice, selective hypomethylation of IL-1β at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases.

2014-10-01 | GSE56452 | GEO

Microglial repopulation reverses cognitive-associated deficits in an Alzheimer’s disease model by restoring the BDNF signaling

Project description:Over the past decade, genetic evidence has demonstrated that microglial dysregulation is likely to play a central role in the development of Alzheimer's disease (AD). As resident immune cells in the brain, microglia become dystrophic and senescent during the chronic progression of AD. To explore whether replenishing the brain with new microglia is beneficial to AD, we employed a CSF1R inhibitor PLX3397 to deplete microglia and induce repopulation after the inhibitor withdrawal in 5xFAD transgenic mice. We observed that microglial repopulation ameliorates AD-associated cognitive deficits, accompanied by elevation of synaptic proteins and hippocampal long-term potentiation (LTP). In addition, microglial morphology is restored after microglial self-renewal, and amyloid pathology is reduced with long-term repopulation but not short-term. Transcriptome analysis showed that repopulating microglia in 5xFAD mice recovers a gene expression profile that is highly similar to microglia from WT mice. Notably, the neurotrophic signaling pathway and hippocampal neurogenesis dysregulated in the AD brain are restored after microglial replenishment. At last, we confirmed that microglial repopulation rescues brain-derived neurotrophic factor (BDNF) expression to contribute to synaptic plasticity. Together, we conclude that microglial self-renewal benefits AD brain by restoring the BDNF neurotrophic signaling pathway. Thus, the proper replenishment of microglia may be an effective and novel therapeutic strategy for ameliorating cognition impairment in AD.

2023-07-24 | GSE223156 | GEO

Type I Interferon Signaling Mediates Microglial Dysfunction and Senescence in Human-Mouse Chimeric Brain Models of Down Syndrome and Alzheimer’s Disease [bulk RNA-seq]

Project description:Microglia are critical for brain development and play a central role in Alzheimer’s disease (AD) etiology. Down syndrome (DS), also known as trisomy 21, is the most common genetic origin of intellectual disability and the most common risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglia in DS brain development and AD in DS (DSAD). Using our new induced pluripotent stem cell (iPSC)-based human microglia-containing cerebral organoid and chimeric mouse brain models, here we report that DS microglia exhibit enhanced synaptic pruning function during brain development. Consequently, electrophysiological recordings demonstrate that DS microglial mouse chimeras show impaired synaptic neurotransmission, as compared to control microglial chimeras. Upon being exposed to human brain tissue-derived soluble pathological tau, DS microglia display dystrophic phenotypes in chimeric mouse brains, recapitulating microglial responses seen in human AD and DSAD brain tissues. Further flow cytometry, single-cell RNA-sequencing, and immunohistological analyses of chimeric mouse brains demonstrate that DS microglia undergo cellular senescence and exhibit elevated type I interferon signaling after being challenged by pathological tau. Mechanistically, we find that shRNA-mediated knockdown of Hsa21-encoded type I interferon receptor genes, IFNARs, rescues the defective DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide in vivo evidence supporting a paradigm shifting theory that human microglia respond to pathological tau with accelerated senescence. Our results further suggest that targeting IFNARs may improve microglial functions during DS brain development and prevent human microglial senescence in DS individuals with AD.

2022-07-08 | GSE189225 | GEO

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