Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer’s disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE241553 | GEO | 2023/11/02
REPOSITORIES: GEO
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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: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 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:Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer’s disease (AD) with APOE4 increasing and APOE2 decreasing risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared to ApoE3 or the absence of ApoE. However, the role of ApoE isoforms in regulating lipid metabolism in the setting of tauopathy is unknown. Here, by using targeted lipidomics coupled with histological analysis, we demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation along with significant perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via administration of the LXR agonist GW3965 reduces lipid droplet accumulation in primary E4 microglia in vitro and GW3965 or Abca1 overexpression strongly attenuates tau pathology, neurodegeneration, and synapse loss in P301S/ApoE4 mice. By immunostaining, bulk and snRNA sequencing, we demonstrate reductions in reactive astrocytes and microglia as well as significant changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids via Abca1 could serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.
2023-12-08 | GSE242693 | GEO
Project description:Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer’s disease (AD) with APOE4 increasing and APOE2 decreasing risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared to ApoE3 or the absence of ApoE. However, the role of ApoE isoforms in regulating lipid metabolism in the setting of tauopathy is unknown. Here, by using targeted lipidomics coupled with histological analysis, we demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation along with significant perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via administration of the LXR agonist GW3965 reduces lipid droplet accumulation in primary E4 microglia in vitro and GW3965 or Abca1 overexpression strongly attenuates tau pathology, neurodegeneration, and synapse loss in P301S/ApoE4 mice. By immunostaining, bulk and snRNA sequencing, we demonstrate reductions in reactive astrocytes and microglia as well as significant changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids via Abca1 could serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.
2023-12-08 | GSE242180 | GEO
Project description:The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Ab42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Ab uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Ab phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant.
2018-05-31 | GSE102956 | GEO
Project description:This study assessed the effects of amino terminal ApoE4 fragments (residues 1-151) on modulating the transcriptome of BV2 microglial cells. Treatment with amino terminal ApoE4 fragments caused the upregulation of nearly four-thousand genes, and further analysis revealed a significant upregulation of genes related to the inflammatory immune response. As a control, an amino terminal ApoE3 fragment was tested and produced a similar but reduced level of upregulation of an identical set of genes. This set of genes affected pathways including Toll receptor signaling, chemokine/cytokine signaling and apoptosis signaling. Additionally, each treatment regulated a unique set of genes. Amino terminal ApoE3 fragments uniquely regulated 14 times as many genes (1,674), many of which are involved in physiological functions within microglia. Amino terminal ApoE4 fragments uniquely upregulated 119 genes, with many of the top upregulated genes having unknown functions. Our results suggest that while amino terminal ApoE3 fragments may serve a more physiological role in microglia amino terminal ApoE4 fragments may activate genes with a more pathological purpose. These data support the hypothesis that the link between harboring the APOE4 allele and dementia risk could be enhanced inflammation through activation of microglia.
2020-07-31 | GSE153454 | GEO
Project description:Recent findings suggest that the human APOE epsilon 4 allele protects against non-alcoholic fatty liver disease, while APOE epsilon 3 promotes hepatic steatosis and steatohepatitis. We performed an untargeted proteome analysis of the liver and identified a great number of proteins differently expressed in obese APOE3 and APOE4 mice. The majority of the proteins up-regulated in APOE3 can be grouped to inflammation and damage-associated response, cytoskeleton and lipid storage. In contrast, those proteins that are up-regulated in APOE4 can be related to intermediate filament modifications, biotransformation and amino acid metabolism. Results of the targeted quantitative RT-PCR and Western blot experiments contribute to the overall finding that APOE3 promotes hepatic steatosis, inflammatory- and damage-associated response signaling and fibrosis in the liver of obese mice. One of the proteins that were up-regulated in obese as well as lean APOE4 compared to APOE3 mice is parvulin 14 (Pin4). Up-regulation of parvulin 14 may be involved in the protection against fatty liver disease evident in the presence of APOE4.
2024-05-21 | PXD033973 | Pride
Project description:The overall goal of our study is to understand the effect of HNE modification on the structure and function of apolipoprotein E3 (apoE3) and apoE4, which play a critical role in brain cholesterol homeostasis. Immunoblots indicated HNE modification of recombinant apoE3 and apoE4 with a major band at ~36 kDa, while LC-MS/MS analysis revealed modification of H140 and H299 in both, and additionally at C112 in apoE3.
2024-08-09 | PXD038105 | Pride
Project description:APOE4 genotype is the strongest risk factor for the pathogenesis of sporadic Alzheimer’s disease (AD), but the detailed molecular mechanism of APOE4-mediated synaptic impairment remains to be determined in human cellular context. In this study, we generated human astrocyte model carrying APOE3 or APOE4 genotype using human induced pluripotent stem cells (iPSCs), in which isogenic APOE4 iPSCs were genome-edited from healthy control APOE3 iPSCs. By transcriptome analysis of human astrocytes between APOE genotypes, we showed the upregulation of an extracellular matrix glycoprotein in human APOE4 astrocytes, which may cause synaptic degeneration in concert with the equivocal reactive character and lipid change. Together, these results demonstrate novel negative impact of human APOE4 astrocyte on synaptic integrity and lead to a promising therapeutic intervention into APOE4-carriers.
2023-08-31 | GSE206314 | GEO