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An Exhausted-Like Microglial Population Accumulates in Aged and APOE4 Genotype Alzheimer’s Brains

ABSTRACT: An Exhausted-Like Microglial Population Accumulates in Aged and APOE4 Genotype Alzheimer’s Brains

PROVIDER: PRJNA1001885 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23500914_1.fastq.gz	Fastqsanger.gz
	SRR23500914_2.fastq.gz	Fastqsanger.gz
	SRR23500915_1.fastq.gz	Fastqsanger.gz
	SRR23500915_2.fastq.gz	Fastqsanger.gz
	SRR23500916_1.fastq.gz	Fastqsanger.gz

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An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer's brains.

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An Exhausted-Like Microglial Population Accumulates in Aged and APOE4 Genotype Alzheimer’s Brains

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Lipid Accumulation Induced by APOE4 Impairs Microglial Surveillance of Neuronal-Network Activity

Project description:Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing late-onset Alzheimer’s disease and its expression in microglia is associated with pro-inflammatory states. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral allele APOE3 is currently unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a distinct metabolic program in microglia that is marked by the accumulation of intracellular neutral lipid stores through impaired lipid catabolism. Importantly, this altered lipid-accumulated state shifts microglia away from homeostatic surveillance and renders APOE4 microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia before and after exposure to neuronal conditioned media, we further established that neuronal soluble cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Pharmacological blockade of lipogenesis in APOE4 microglia is sufficient to diminish intracellular lipid accumulation and restore microglial homeostasis. Remarkably, unlike APOE3 microglia that support neuronal network activity, co-culture of APOE4 microglia with neurons disrupts the coordinated activity of neuronal ensembles. We identified that through decreased uptake of extracellular fatty acids and lipoproteins, APOE4 microglia disrupts the net flux of lipids which results in decreased neuronal activity via the potentiation of the lipid-gated K+ channel, GIRK3. These findings suggest that neurological diseases that exhibit abnormal neuronal network-level disturbances may in part be triggered by impairment in lipid homeostasis in non-neuronal cells, underscoring a novel therapeutic route to restore circuit function in the diseased brain.

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Spatial transcriptomics Reveals Impact of APOE4 Allele on α-Synuclein Aggregation and Cell-Cell Communication in Lewy Body Dementia

Project description:We performed spatial transcriptomics to understand a-synuclein pathology-specific molecular profiles and cell-cell communication in human Lewy Body Dementia (LBD) brains. We included APOE3/3 and APOE3/4 LBD brains to dissect APOE4 impact on a-synuclein pathologies. Our analysis showed the key dysregulated pathways around the pathology comparing LBD brains to control brains, which further exacerbated by APOE4.

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Differential gene expression in APOE3 and APOE4 gene targeted replacement mice

Project description:The aim of the study was to investigate hepatic gene expression profiles differentially regulated by the APOE genotype in gene targeted replacement mice. The APOE4 genotype is associated with increased mortality in the elderly and is an independent risk factor for age-dependent chronic diseases. However, little is known about the underlying mechanisms and molecular targets involved in the APOE4-risk association. As APOE is centrally involved in lipid and cholesterol metabolism and in large part is produced in the liver, we analyzed hepatic RNA profiles of APOE4- and APOE3-expressing mice. 2 groups of 5 animals with 1 liver extract per animal. Mice were homozygous for a human APOE3 or APOE4 gene targeted replacement of the endogenous mouse Apoe gene (B6.129P2-Apoetm2(APOE*3)Mae N8 or B6.129P2-Apoetm3(APOE*4)Mae N8, Taconic Transgenic ModelsM-bM-^DM-", http://www.taconic.com/wmspage.cfm?parm1=2542), purchased at the age of 6-8 weeks, strain C57BL/6, 3 months old at the performance of the microarray, 6 weeks on a high-fat diet containing 41% energy from milk fat and 2 g/kg cholesterol.

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Single-cell RNA-seq of human breast tumor samples with exhausted and non-exhausted immune environments

Project description:Fresh human breast tumor tissue was dissociated into single cells and viably frozen. Patient samples were annotated as having an ""exhausted"" or ""non-exhausted"" immune environment based on CyTOF characterization of T cell phenotypes (Wagner et al, Cell 2019). 14 samples (7 exhausted, 7 non-exhausted) were selected for scRNA-seq (without prior cell type enrichment) with the goal to compare the two immune environment types and to comprehensively characterize exhaustion-associated features of the tumor microenvironment.

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Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4 [RNA-seq]

Project description:Microglia modulate their cell state in response to various stimuli. Changes to cellular lipids often accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer’s disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in cell state. In fact, both triglyceride biosynthesis and catabolism are necessary for the activation-induced transcription and the secretion of inflammatory cytokines and chemokines as well as the changes in phagocytosis of many substrates including the amyloid-beta peptide. In microglia harboring the Alzheimer’s disease risk APOE4 genotype, inhibiting triglyceride biosynthesis modifies the transcription of immune response genes and attenuates disease-associated transcriptional states. In addition, this inhibition rescues microglial surveillance defects observed in slices from APOE4 humanized transgenic mice. Together, our findings establish that modulating triglyceride metabolism can be used to tune microglial immunometabolism in response to extrinsic activation and in APOE4-associated disease.

2025-05-29 | GSE286874 | GEO

APOE3 and APOE4 Human Astrocytes Differentially Modulate Alzheimer’s Disease Pathology and Microglial Responses in Chimeric Mice

Project description:To investigate how APOE3 and APOE4 human iPSC-derived astrocytes influence the gene expression profile of the mouse host microglia in vivo, we performed bulk RNA sequencing of cortical regions adjacent to transplanted astrocytes in AD chimeric mice. Human iPSC-derived astrocytes (APOE3 or APOE4) were transplanted into neonatal Alzheimer's disease model mice and analyzed 6-7 months post-transplantation. Mouse-specific transcripts were analyzed to compare the transcriptomic profiles of host microglia in AD chimeric mice engrafted with APOE4 versus APOE3 human astrocytes.

2026-07-09 | GSE335500 | GEO

Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer’s disease

Project description:Cells in the cortex of mice expressing apoE3 or apoE4 in the microglia were isolated and subjected to the single-cell RNA seq to investigate the effects of microglia/CNS-associated macrophages (CAMs) apoE on the brain transcriptomic profiles. Our data revealed that microglia/CAM-expressed apoE3 promotes antigen presentation and immune patnways, whereas apoE4 down-regulates complement and promotes stress-related responses.

2023-11-02 | GSE241553 | GEO

ApoE4 Drives Microglial Lipid Dysregulation in Alzheimer’s Disease via Epigenetic Reprogramming of the AsxL1/LXRα–H3K4me3 Axis

Project description:Background The ε 4 allele of apolipoprotein E gene (ApoE) stands as the greatest genetic risk factor for late-onset Alzheimer’s disease (AD). Although microglia accumulating lipid droplets (LDAM) have been implicated in AD pathogenesis, the mechanistic link between ApoE4 and microglial lipid dysregulation remains elusive. Methods We employed a multi-omics approach, combining snRNA-seq and locus-specific epigenetic analysis, alongside microglia-specific gene manipulation in ApoE-targeted replacement (TR) mice. Primary microglia were challenged with cholesterol to simulate lipid overload conditions. Results In mid-life ApoE4-TR mice, microglia within the dentate gyrus developed pronounced lipid droplet accumulation, concurrent with impaired Aβ clearance and a pro-inflammatory shift. snRNA-seq unveiled a unique microglial cluster in ApoE4 mice, enriched for lipid-metabolism genes and marked by the pronounced downregulation of the hub gene AsxL1. Mechanistically, ApoE4 attenuated the AsxL1–LXRα interaction, leading to reduced H3K4me3 occupancy at promoters of lipid-efflux genes such as Abca1. Crucially, CRISPR-mediated, microglia-specific overexpression of AsxL1 restored H3K4me3 levels, normalized cholesterol efflux, and rescued Aβ phagocytic deficits in vivo. Conclusions Our findings define an epigenetic pathway whereby ApoE4 drives microglial dysfunction via the AsxL1–LXRα–H3K4me3 axis, fostering the LDAM phenotype. Enhancing AsxL1 function presents a promising therapeutic avenue for countering ApoE4-mediated pathogenesis in AD.

2026-02-16 | GSE319246 | GEO

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