Single-nucleus RNA-seq analysis of whole brains from 5xFAD mice with microglia-specific CD31 knockdown
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE331294 | GEO | 2026/05/23
REPOSITORIES: GEO
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Project description:Microglia are closely linked to the pathogenesis of Alzheimer's disease (AD), yet the mechanisms by which they influence AD pathogenesis remain poorly defined. Here, we found that CD31 is predominantly expressed in microglia (rather than in neurons or astrocytes) and that its expression is notably elevated in microglia from AD patients and animal models. Microglia-specific knockdown of CD31 in 5xFAD mice significantly normalized the dysregulated expression of multiple gene sets in microglia. This was accompanied by inhibited microglial hyperactivation, a reduced proportion of disease-associated microglia (DAM), decreased Aβ plaque deposition, mitigated inflammatory responses, alleviated synaptic damage, and ultimately improved cognitive functions. Mechanistically, these effects were mediated by reduced CD31-dependent recruitment of Src homology phosphatase 2 (SHP2), which led to a decreased dephosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) and thereby an enhanced activation. This cascade resulted in increased transcription of membrane metalloendopeptidase (MME) and enhanced Aβ clearance. Collectively, this study identifies microglial CD31 as a critical regulator of AD pathogenesis via the SHP2–STAT3–MME axis and highlights targeting CD31 as a potential novel therapeutic strategy for AD
2026-05-23 | GSE331306 | GEO
Project description:Single nucleus RNA-Seq (snRNA-Seq) is used as an alternative to single cell RNA-Seq, as it allows transcriptomic profiling of frozen tissue. However, it is unclear whether snRNA-Seq is able to detect cellular state in human tissue. Indeed, snRNA-Seq analyses of human brain samples have failed to detect a consistent microglial activation signature in Alzheimer’s Disease. Our comparison of microglia from single cells and single nuclei of four human subjects revealed that, while the majority of genes showed similar relative abundances in cells and nuclei, a small population of genes (~1%) was depleted in nuclei compared to whole cells. This population was enriched for genes previously implicated in microglial activation, including APOE, CST3, SPP1, and CD74, comprising 18% of previously-identified microglial disease-associated genes. Given the low sensitivity of snRNA-Seq to detect many activation genes, we conclude that snRNA-Seq is not suited to detecting cellular activation in microglia in human disease.
2020-09-29 | GSE153807 | GEO
Project description:Microglial endolysosomal dysfunction is strongly implicated in neurodegeneration. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimer’s Disease (AD) models and in human AD brain, and that the onset of this state is emphasised in females. Cst7 (Cystatin F) is among the most highly unregulated genes in these microglia. However, the sex-specific function of Cst7 in neurodegenerative disease is not understood. Here, we crossed Cst7 -/- mice with the App NL-G-F mouse to test the role of Cst7 in a model of amyloid-driven AD.
2023-11-22 | E-MTAB-13360 | biostudies-arrayexpress
Project description:Blood protein extravasation through a disrupted blood–brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type 1 interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer’s disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.
2023-06-02 | GSE229372 | GEO
Project description:<p>Microglia, the brain’s primary resident immune cells, can assume various phenotypes with diverse functional outcomes on brain homeostasis. In Alzheimer’s disease (AD), where microglia are a leading causal cell type, the identity of microglia subsets that drive neurodegeneration remains unresolved. Here, we discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a subset of microglia with neurodegenerative outcomes. ISR is activated in AD-associated microglia subsets, including the ultrastructurally distinct “dark” microglia linked to pathological synapse loss. Activation of ISR in microglia is sufficient to induce early features of dark microglia. In AD models, microglial ISR exacerbates neurodegenerative pathologies, such as Tau and synapse loss, while inhibiting microglial ISR ameliorates them. Mechanistically, we present evidence that ISR in microglia promotes the secretion of toxic long-chain lipids that impair neuron homeostasis and survival in vitro. Accordingly, pharmacological inhibition of ISR and lipid synthesis ameliorates synapse loss in AD models. Our results demonstrate that activation of ISR within microglia represents a pathway contributing to neurodegeneration and suggest that this may be sustained, at least in part, by the secretion of toxic long-chain lipids from ISR-activated microglia. </p>
2024-12-20 | MTBLS11942 | MetaboLights
Project description:In Alzheimer’s disease, dysfunctional microglia possess abnormal immunometabolic features that cause neuronal/synaptic damage and aggravate pathology. A critical question is how to reverse or fine-tune abnormal microglial metabolism towards beneficial immunometabolic outcomes. A major metabolic intervention strategy to raise circulating ketone levels for health benefits, such as by consumption of a ketogenic diet 1, fasting, or other approaches collectively called ketotherapeutics, has raised a great deal of interest, but its effects on microglia are not well understood. Our previous in vitro study showed that β-hydroxybutyrate (BHB), a major ketone body, reverses multiple pathological features of amyloid-β oligomer (AβO)-activated human microglia. In the current study, we tested the in vivo effects of BHB on microglia and synaptic plasticity in the 5xFAD Alzheimer’s disease mouse model. To capture the metabolic impact of BHB on microglia, we employed a “subacute” 1-week regimen of daily intraperitoneal injection of BHB (250 mg/kg), which induced brief and mild episodic (daily) ketosis. This short regimen was able to mitigate pro-inflammatory microglia activation linked to NLRP3 inflammasome formation, and reduce brain amyloid-β deposition by enhancing phagocytosis. Remarkably, this regimen mitigated the deficits of hippocampal long-term depression but not long-term potentiation, and this effect was linked to suppression of the inflammasome-generated cytokine IL-1β. Our results suggest that short-term BHB treatment may ameliorate microglial abnormalities and microglia-regulated synaptic deficits in Alzheimer’s disease. Because beneficial results were achieved with mild episodic BHB elevation alone without diet restriction and without the need of feeding a KD, our results have significant implications to human ketotherapeutics. As KDs are known for poor compliance and low sustainability due to their restrictive nature, our study opens the possibility for alternative ketogenic approaches that are less restrictive, potentially safer, and easier for compliance than a KD, such as short-term BHB injections or dietary ketone esters, a translatable form of induced ketosis.
2024-08-31 | GSE269488 | GEO
Project description:Alzheimer’s disease (AD) is the most prevalent neurodegenerativedisorder. Currently, anti-amyloid antibody treatments modestly slow disease progression in milddementia due to AD.Emerging evidence shows that homeostatic dysregulation of the brainimmune system, especially that orchestrated by microglia, plays a significant role in the onset andprogression of the disease, including an increase in neuroinflammation and oxidative stress.Thus,a major question is how to modulate the phenotype and function of microglia to treat AD.Xenongas (Xe) is a noble gas used in human patients as an anesthetic and neuroprotectant in treatingbrain injuries. Xe penetratestheblood-brain barrier, which can make it an effective therapeutic.WeidentifiedthatXeinhalationpolarizesmouse and human microglia towards an intermediatestate of activation that we have termedas‘pre-MGnD’ in anacute neurodegeneration model andmouse models with AD-like pathology, i.e.,5xFAD (amyloid) and P301S (tau). This microglialphenotypic transition enhanced amyloid plaque compaction and reduced dystrophic neurites.Moreover, Xe inhalation reduced brain atrophy neuroinflammationand improved nest-buildingbehavior in APOE4:P301S mice. Mechanistically, Xe inhalation polarizes homeostatic microgliatoward a pre-MGnD state via IFNsignaling that maintains the microglial phagocytic responsewhile suppressing its pro-inflammatory properties. These resultssupport the translation of Xeinhalation as a novel approach to treatingAD.
2025-01-15 | GSE271472 | GEO
Project description:Alzheimer’s disease (AD) is the most prevalent neurodegenerativedisorder. Currently, anti-amyloid antibody treatments modestly slow disease progression in milddementia due to AD.Emerging evidence shows that homeostatic dysregulation of the brainimmune system, especially that orchestrated by microglia, plays a significant role in the onset andprogression of the disease, including an increase in neuroinflammation and oxidative stress.Thus,a major question is how to modulate the phenotype and function of microglia to treat AD.Xenongas (Xe) is a noble gas used in human patients as an anesthetic and neuroprotectant in treatingbrain injuries. Xe penetratestheblood-brain barrier, which can make it an effective therapeutic.WeidentifiedthatXeinhalationpolarizesmouse and human microglia towards an intermediatestate of activation that we have termedas‘pre-MGnD’ in anacute neurodegeneration model andmouse models with AD-like pathology, i.e.,5xFAD (amyloid) and P301S (tau). This microglialphenotypic transition enhanced amyloid plaque compaction and reduced dystrophic neurites.Moreover, Xe inhalation reduced brain atrophy neuroinflammationand improved nest-buildingbehavior in APOE4:P301S mice. Mechanistically, Xe inhalation polarizes homeostatic microgliatoward a pre-MGnD state via IFNsignaling that maintains the microglial phagocytic responsewhile suppressing its pro-inflammatory properties. These resultssupport the translation of Xeinhalation as a novel approach to treatingAD.
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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 | GSE189226 | GEO
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