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A novel microglial transcription profile is driven by sex and APOE4 interactions in both mouse and human models of Alzheimer’s disease

ABSTRACT: Using a transgenic mouse model of AD that expresses human APOE, we identify a unique transcriptional profile associated with APOE4 expression. We also show a sex and APOE interaction, such that both female sex and APOE4 drive expression of this gene profile. We then confirm these findings in human cells, using microglia derived from induced pluripotent stem cells.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE163857 | GEO | 2021/09/21

REPOSITORIES: GEO

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

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2023-11-02 | GSE241553 | 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.

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Domino-like Effect of C112R Mutation on APOE4 Aggregation and Its Suppression by Alzheimer’s Disease Drug Candidate

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2023-07-20 | PXD036416 | Pride

APOE4 retinal microglia remain homeostatic in glaucoma.

Project description:The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer’s disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here we find that in two mouse glaucoma models and in human glaucomatous retinas, microglia transition to a neurodegenerative (MGnD) phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3). Mice in which Apoe was targeted in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss despite elevated intraocular pressure (IOP). Similar to Apoe–/– retinal microglia, APOE4 microglia did not upregulate MGnD genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma, and that the APOE-Galectin-3 signaling pathway can be targeted to treat this blinding disease.

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A novel microglial transcription profile is driven by sex and APOE4 interactions in both mouse and human models of Alzheimer’s disease

Project description:A novel microglial transcription profile is driven by sex and APOE4 interactions in both mouse and human models of Alzheimer’s disease

| PRJNA687763 | ENA

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.

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Differential gene expression in APOE3 and APOE4 gene targeted replacement mice

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2023-04-08 | PXD041205 | Pride

The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation

Project description:Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. We sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration, and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation, but not Tau pathology. Single-nucleus RNA-sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.

2023-09-21 | GSE217854 | GEO

APOE4-dependent transcriptome changes in human iPSC-derived astrocytes

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

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