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The human ApoE4 variant reduces functional recovery and neuronal sprouting after incomplete spinal injury in male mice

ABSTRACT: Patients carrying one or two ApoE4 alleles suffer from worse functional recovery after spinal cord injury. Using transgenic mice expression human ApoE3 or ApoE4 we investigated potential cellular mechanisms of reduced recovery after spinal cord injury. Bulk RNA sequencing of the spinal cord lesion site followed by pathway enrichment analysis predicts that ApoE4 mice have a higher inflammatory and extracellular matrix remodeling activity 7 days after spinal cord injury. Contrary, higher activities for neuronal projection and action potential patways were predicted in the ApoE3 mice at 21 days after injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE164688 | GEO | 2021/02/05

REPOSITORIES: GEO

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Synj 1 modulates functional recovery after motor-incomplete spinal cord injury in male mice carriers of human ApoE4.

Project description:Apolipoprotein E epsilon 4 (ApoE4) is the second most common variant of ApoE, being present in ~14% of population. Clinical reports identify ApoE4 as a genetic risk factor for poor outcomes after traumatic SCI and the spinal cord disease (SCD) cervical myelopathy. To date, there are no interventions to mitigate the potent effects of ApoE4 to reduce recovery of function after SCI/D. Studies in human and mouse brain link ApoE4 to elevated levels of synaptojanin 1 (synj1), a lipid phosphatase that dephosphorylates phosphoinositol 4,5-bisphosphate (PIP2) to inositol 4-monophosphate (PIP1). Synj1 regulates rearrangements of the cytoskeleton and the endocytosis and trafficking of synaptic vesicles. We report here that, as compared to ApoE3 mice, levels of synj1 mRNA and protein were elevated in spinal cords from healthy ApoE4 mice associated with lower PIP2 levels. Using a moderate severity model of contusion SCI in mice, we found that genetic reduction of syn1 improved locomotor function recovery at 14 days after SCI in ApoE4 mice without altering spared white matter. Genetic reduction of synj1 did not alter locomotor recover of ApoE3 mice after SCI. Bulk RNA-sequencing revealed that at 14 days after SCI in ApoE4 mice, genetic reduction of synj1 upregulated genes involved in glutaminergic synaptic transmission just above and below the lesion. Overall, our findings provide evidence for a link between synj1 to poor outcomes after SCI in ApoE4 mice through mechanisms that remain speculative but may include greater function of excitatory glutaminergic synapses.

2023-08-09 | GSE227291 | GEO

The human ApoE4 variant reduces functional recovery and neuronal sprouting after incomplete spinal injury in male mice

Project description:The human ApoE4 variant reduces functional recovery and neuronal sprouting after incomplete spinal injury in male mice

| PRJNA691563 | ENA

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

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

Project description:Cells in the cortex of mice expressing apoE3 or apoE4 in the microglia were isolated and subjected to the single-cell RNA seq to investigate the effects of microglia/CNS-associated macrophages (CAMs) apoE on the brain transcriptomic profiles. Our data revealed that microglia/CAM-expressed apoE3 promotes antigen presentation and immune patnways, whereas apoE4 down-regulates complement and promotes stress-related responses.

2023-11-02 | GSE241553 | 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

APOE4 cell-specific mechanisms underlying cerebrovascular disorder precede neuronal and synaptic dysfunction and cognitive deficits in mice

Project description:We performed single-nucleus RNA-sequencing of the cortex of APOE3 and APOE4 knock-in (KI)flox/flox mice to investigate the effects of human APOE4 gene on cell-specific signaling mechanisms at the BBB and in the brain.

2022-08-22 | GSE185063 | GEO

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

Project description:The development of treatment for Alzheimer’s Disease (AD) is hindered by a limited understanding of its structural basis. Apolipoprotein E (APOE) ε4 genotype is the most important risk factor for late-onset AD. APOE4 differs from the APOE3 isoform by a single mutation, C112R. Here, we employ crystallography, biophysical methods and computer simulations to dissect the “domino-like” effect of C112R substitution on APOE4 behaviour. We found that the mutation induces long-distance (>15 Å) conformational changes leading to geometrically distinct T-shaped dimeric unit of APOE4 compared to APOE3. By mutagenesis, we demonstrate that the APOE4 unit is more prone to aggregation than that of the APOE3. AD drug candidate tramiprosate and metabolite 3-sulfopropanoic acid induce APOE3-like conformational behaviour in APOE4 and suppress its aggregation propensity. Omics analysis of APOE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage product of excess cholesterol. Our results connect the APOE4 structure with its aggregation propensity, which can be further exploited in drug development for neurodegeneration and ageing.

2023-07-20 | PXD036416 | Pride

Differential gene expression in APOE3 and APOE4 gene targeted replacement mice

2012-12-15 | GSE42930 | 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

Quantitative proteomic analysis reveals apoE4-dependent phosphorylation of the actin regulating protein VASP

Project description:Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s Disease (AD). While neurons generally produce a minority of the apoE in the central nervous system, neuronal expression of apoE increases dramatically in response to stress and is sufficient to drive pathology. Currently, the molecular mechanisms of how apoE4 expression may regulate pathology are not fully understood. Here we expand upon our previous studies measuring the impact of apoE4 on protein abundance to include the analysis of protein phosphorylation and ubiquitylation signaling in isogenic Neuro-2a cells expressing apoE3 or apoE4. We find that apoE4 expression results in the dramatic increase in VASP S235 phosphorylation in a PKA-dependent manner. This phosphorylation results in the loss of VASP interactions with numerous actin cytoskeletal and microtubular proteins. Reduction of VASP S235 phosphorylation via PKA inhibition results in a significant increase in filopodia formation and neurite outgrowth in apoE4-expressing cells to levels beyond that of apoE3. Our results highlight the pronounced and diverse impact of apoE4 on multiple modes of protein regulation and identify potential therapeutic targets to restore apoE4-related cytoskeletal defects.

2023-04-08 | PXD041205 | Pride

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