Effect of LRP1 deletion in vascular mural cells and APOE gentotype on gene expression in mouse brains
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ABSTRACT: To investigate the apoE isoform-dependent role of vascular mural cell (VMC)-LRP1, we generated VMC-specific LRP1 knockout mice (smLrp1-/-), followed by breeding these mice with either APOE3-targeted replacement (TR) or APOE4-TR mice We then performed gene expression profiling analysis using data obtained from RNA-seq of cortical samples from 4 different mouse models
Project description:Here we analyze the transcriptional profiles of homogenized lungs resected from APOE2, APOE3, and APOE4 knock-in mice on day 4 post infection with SARS-CoV-2 MA10. This experiment validated a prior RNA-seq experiment revealing blunted adaptive immunity in APOE2 and APOE4 mice during COVID-19 progression.
Project description:The apolipoprotein E (APOE) gene is the strongest genetic risk modifier for Alzheimer's disease (AD), with the APOE4 allele increasing risk and APOE2 decreasing it compared to the common APOE3 allele. Using single-nuclei RNA sequencing of the temporal cortex from APOE2 carriers, APOE3 homozygotes, and APOE4 carriers, we found that AD-associated transcriptomic changes were highly APOE genotype-dependent. Comparing AD with controls, APOE2 carriers showed upregulated synaptic and myelination-related pathways, preserving synapses and myelination at the protein level. Conversely, these pathways were downregulated in APOE3 homozygotes, resulting in reduced synaptic and myelination proteins. In APOE4 carriers, excitatory neurons displayed reduced synaptic pathways similar to APOE3, but oligodendrocytes showed upregulated myelination pathways like APOE2. However, their synaptic and myelination protein levels remained unchanged or increased. APOE4 carriers also showed increased pro-inflammatory signatures in microglia but reduced responses to amyloid-β pathology. These findings reveal APOE genotype-specific molecular alterations in AD across cell types.
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.
Project description:We examined the impact of Abca1 deficiency and APOE isoform expression on the response to TBI using 3-months-old, human APOE3+/+ (E3/Abca1+/+) and APOE4+/+ (E4/Abca1+/+) targeted replacement mice, and APOE3+/+ and APOE4+/+ mice with only one functional copy of the Abca1 gene (E3/Abca1+/-; E4/Abca1+/-). TBI-treated mice received a craniotomy followed by a controlled cortical impact (CCI) brain injury in the left hemisphere; sham-treated mice received the same surgical procedure without the impact. We performed RNA-seq using samples from cortices and hippocampi collected at 14 days post-injury, followed by genome-wide differential gene expression analysis.
Project description:Vascular cell-enriched cells in the cortex of mice expressing apoE3 or apoE4 in the liver were isolated and subjected to the single-cell RNA seq to investigate the effects of peripheral apoE on the brain transcriptomic profiles. Our data revealed that liver-expressed apoE4 reduced astrocyte endfeet and promoted immune responses in the endothelial cells as welll as increases vessel-associated gliosis. Genes involved in IGF signaling, tight junction formation, actin cytoskeleton signaling, and maintenance of endothelial barrier function were up-regulated in the endothelial cells of mice expressing apoE3 in the liver.
Project description:Here we analyze the transcriptional profiles of homogenized lungs resected from young female APOE2, APOE3, and APOE4 knock-in mice on day 4 post infection with SARS-CoV-2 MA10. Weighted gene co-expression analysis identified gene modules enriched for genes implicated in T and B cell activation to be downregulated in APOE2 and APOE4 mice during COVID-19 progression.
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.
Project description:Here we analyze the transcriptional profiles of homogenized lungs resected from APOE2, APOE3, and APOE4 knock-in mice in the absence of infection (day 0) and on days 2 and 4 post infection with SARS-CoV-2 MA10. Weighted gene co-expression analysis identified gene modules enriched for genes implicated in T and B cell activation to be downregulated in APOE2 and APOE4 mice during COVID-19 progression.