Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4 [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1210469 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR31990407_1.fastq.gz | Fastqsanger.gz | |||
| SRR31990407_2.fastq.gz | Fastqsanger.gz | |||
| SRR31990408_1.fastq.gz | Fastqsanger.gz | |||
| SRR31990408_2.fastq.gz | Fastqsanger.gz |
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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
Project description:Here we elucidate the effect of Alzheimer’s disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9 and APPswe, on functionality of human microglia. We present a physiologically relevant high-yield protocol for producing human microglia-like cells (iMGLs) from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to recreate microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.
2019-10-08 | GSE135707 | GEO
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.
2022-05-19 | GSE203019 | GEO
Project description:Several genetic risk factors for Alzheimer’s Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aβ (fAβ) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.
2024-02-01 | GSE254205 | GEO
Project description:Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer’s Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.
2024-10-25 | GSE248020 | GEO
Project description:The strongest risk factors for Alzheimer’s disease (AD) include the 4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that the R47H variant induces neurodegeneration in 9- to- 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.
2024-08-22 | PXD053544 | Pride
Project description:APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD) with increased odds ratios in females. Targeting amyloid plaques show modest improvement in male non-APOE4 carriers. Leveraging single cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female AD patients, we identify a new subset of neutrophils, interacting with microglia associated with cognitive impairment. This phenotype is defined by increased IL-17 and IL-1 co-expressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE e4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFb, and immune checkpoints including LAG-3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored microglial response to neurodegeneration (MGnD), limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of MGnD phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE e4 female carriers with cognitive impairment.
2024-06-04 | GSE262632 | GEO
Project description:APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD), with increased odds ratios in females. Targeting amyloid plaques shows modest improvement in male non-APOE4 carriers. Leveraging single-cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry, and validation in two independent cohorts of APOE4 female AD patients, we identify a new subset of neutrophils interacting with microglia associated with cognitive impairment. This phenotype is defined by increased IL-17 and IL-1 co-expressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE e4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFB and immune checkpoints, including LAG-3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored the microglial response to neurodegeneration (MGnD), limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of MGnD phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE e4 female carriers with cognitive impairment.
2024-06-04 | GSE260461 | GEO
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.
2012-12-15 | E-GEOD-42930 | biostudies-arrayexpress
Project description:Lipid Accumulation Induced by APOE4 Impairs Microglial Surveillance of Neuronal-Network Activity
| PRJNA838125 | ENA