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Microglia gravitate toward amyloid plaques surrounded by externalized phosphatidylserine via TREM2

ABSTRACT: iPSC-derived brain organoids with microglial cells (assembloids) were used for this study. We used single cell RNA sequencing (scRNA-seq) to analyze the difference between APOE3 and APOE4 genotypes

ORGANISM(S): Homo sapiens

PROVIDER: GSE220690 | GEO | 2023/09/01

REPOSITORIES: GEO

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Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer’s Disease Model

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

Gene expression profile of either Dead neuron+/Fcrls+/CD11b+/Ly6C- or Dead neuron-/Fcrls+/CD11b+/Ly6C- microglia from the brain II

Project description:We used bulk RNA sequencing to investigate the molecular signature of phagocytic and non-phagocytic microglia affected by APOE isoform (APOE3-KI vs. APOE3-cKO vs. APOE4-KI vs. APOE4-cKO)

2023-07-31 | GSE234350 | GEO

Peripherally-expressed apoE4 impairs brain functions and exacerbates amyloid pathogenesis by compromising cerebrovascular functions

Project description:The apolipoprotein E4 (APOE4) gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE is a lipid carrier abundantly expressed in both brain and periphery. As peripheral apoE is separated from brain apoE by the blood-brain barrier, it remains unclear whether peripheral apoE impacts brain functions and AD pathogenesis. To investigate this, we developed novel mouse models that conditionally express human APOE3 or APOE4 only in the liver with no detectable apoE in the brain. We found that liver-expressed apoE4 compromised synaptic plasticity and cognitive behaviors likely by impairing cerebrovascular functions. Remarkably, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate a pathogenic effect of peripheral apoE4, providing strong rationale for targeting peripheral apoE to treat AD.

2022-06-15 | GSE125501 | GEO

Gene co-expression networks identify Trem2 and Tyrobp as major hubs in human APOE expressing mice following traumatic brain injury.

Project description:To determine if there is an APOE isoform-specific response to TBI we performed controlled cortical impact on 3-month-old mice expressing human APOE3 or APOE4 isoforms. Following injury, we used several behavior paradigms to test for anxiety and learning and found that APOE3 and APOE4 targeted replacement mice demonstrate cognitive impairments following moderate TBI. Transcriptional profiling 14 days following injury revealed a significant effect of TBI, which was similar in both genotypes.

2017-07-29 | GSE102014 | GEO

Microglia use TAM receptors to detect and engulf amyloid beta plaques

Project description:Two microglial TAM receptor tyrosine kinases - Axl and Mer - have been linked to Alzheimer’s disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer’s disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia is coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer’s disease, sIngle cell RNAseq analysis comparing wild type microglia with those with Axl and Mer deficiency reveals a similar disease state transitional program of microglia but a dampened differential expression of numerous AD siganture genes in microglia lacking TAM receptors. In line with the transcriptomic data, using two-photon microscopy, we show that genetic ablation of Axl and Mer results in microglia that are unable to normally detect, respond to, organize, or phagocytose amyloid beta plaques. These major deficits notwithstanding, and contrary to expectation, TAM-deficient APP/PS1 mice develop fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques, and that TAM-driven microglial phagocytosis does not constrain, but rather promotes, plaque development.

2021-02-25 | GSE160523 | GEO

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.

2012-12-15 | E-GEOD-42930 | biostudies-arrayexpress

Gene expression profile of Fcrls+/CD11b+/Ly6C- microglia from the brain II

Project description:We used bulk RNA sequencing to investigate the molecular signature of microglia affected by microglia-specific APOE isoform (APOE3 vs. APOE4) in both WT and P301S mice

2023-07-31 | GSE234391 | GEO

Transcriptome Analyses in BV2 microglial cells following treatment with amino-terminal fragments of apolipoprotein E

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

Gene expression profile of either Dead neuron+/Fcrls+/CD11b+/Ly6C- or Dead neuron-/Fcrls+/CD11b+/Ly6C- microglia from the brain I

Project description:We used bulk RNA sequencing to investigate the molecular signature of phagocytic and non-phagocytic microglia affected by APOE isoform (APOE3-KI vs. APOE4-KI)

2023-07-31 | GSE234348 | GEO

A SAGE approach to discovery of apolipoprotein E4 allele-specific genes involved in increased risk in Alzheimer disease

Project description:APOE4 allele is a major risk factor for late-onset Alzheimer disease (AD). The mechanism of action of APOE in AD remains unclear. To study the effects of APOE alleles on gene expression in AD, we have analyzed the gene transcription patterns of human hippocampus from APOE3/3, APOE3/4, APOE4/4 AD patients and normal control using Serial Analysis of Gene Expression (SAGE). Using SAGE, we found gene expression patterns in hippocampus of APOE3/4 and APOE4/4 AD patients differ substantially from those of APOE3/3 AD patients. APOE3/4 and APOE4/4 allele expression may activate similar genes or gene pools with associated functions. APOE4 AD alleles activate multiple tumor suppressors, tumor inducers and negative regulator of cell growth or repressors that may lead to increased cell arrest, senescent and apoptosis. In contrast, there is decreased expression of large clusters of genes associated with synaptic plasticity, synaptic vesicle trafficking (metabolism) and axonal/neuronal outgrowth. In addition, reduction of neurotransmitter receptors and Ca++ homeostasis, disruption of multiple signal transduction pathways, and loss of cell protection and notably mitochondrial oxidative phosphorylation/energy metabolism are associated with APOE3/4 and APOE4/4 AD alleles. These findings help define the mechanisms that APOE4 contribute increased risk for AD and identify new candidate genes conferring susceptibility to AD. Keywords: Serial Analysis of Gene Expression (SAGE); Apolipoprotein E (APOE3/3, APOE3/4, APOE4/4); Alzheimer disease; Hippocampus; apoptosis; signal pathways

2007-01-13 | GSE6677 | GEO

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