Limited effects of an eIF2αS51A allele on neurological impairments in the 5xFAD mouse model of Alzheimer’s disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50521 | GEO | 2013/09/10
SECONDARY ACCESSION(S): PRJNA217853
REPOSITORIES: GEO
Similar Datasets
Project description:Transcriptome analysis of hippocampal RNA samples from wild-type, 5xFAD, 5xFAD;eIF2α+/S51A and eIF2α+/S51A mice Our transcriptome analyses showed clear transcriptional alterations in hippocampi of 5xFAD compared to wild type mice that were not corrected by the eIF2αS51A allele. Hemizygous 5xFAD mice, which were on a genetic background of B6/SJL, were crossed with eIF2α+/S51A mice (C57BL/6J background), to generate the offspring that was analyzed in the microarray. Hippocampal samples of 12 mice (4 groups: wild-type, 5xFAD, 5xFAD;eIF2α+/S51A and eIF2α+/S51A) were processed using Affymetrix Mouse Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool. No technical replicates were performed.
2013-09-10 | E-GEOD-50521 | biostudies-arrayexpress
Project description:Alzheimer's disease (AD) has been associated with increased phosphorylation of the translation initiation factor 2α (eIF2α) at serine 51. Increased phosphorylation of eIF2α alters translational control and may thereby have adverse effects on synaptic plasticity, learning, and memory. To analyze if increased levels of p-eIF2α indeed promote AD-related neurocognitive impairments, we crossed 5xFAD transgenic mice with an eIF2α(S51A) knock-in line that expresses the nonphosphorylatable eIF2α variant eIF2α(S51A). Behavioral assessment of the resulting mice revealed motor and cognitive deficits in 5xFAD mice that were, with the possible exception of locomotor hyperactivity, not restored by the eIF2α(S51A) allele. Telemetric intracranial EEG recordings revealed no measurable effects of the eIF2α(S51A) allele on 5xFAD-associated epileptic activity. Microarray-based transcriptome analyses showed clear transcriptional alterations in 5xFAD hippocampus that were not corrected by the eIF2α(S51A) allele. In contrast to prior studies, our immunoblot analyses did not reveal increased levels of p-eIF2α in the hippocampus of 5xFAD mice, suggesting that elevated p-eIF2α levels are not a universal feature of AD models. Collectively, our data indicate that 5xFAD-related pathologies do not necessarily require hyperphosphorylation of eIF2α to emerge; they also show that heterozygosity for the nonphosphorylatable eIF2α(S51A) allele has limited effects on 5xFAD-related disease manifestations.
| S-EPMC4391319 | biostudies-literature
Project description:we conducted a detailed phenotypic characterization of the 5xFAD model on a congenic C57BL/6J strain background, across its lifespan – including a seldomly analyzed 18-month old time point to provide temporally correlated phenotyping of this model and a template for characterization of new models of LOAD as they are generated. This comprehensive analysis included quantification of plaque burden, Aβ biochemical levels, and neuropathology, neurophysiological measurements and behavioral and cognitive assessments, and evaluation of microglia, astrocytes, and neurons. Analysis of transcriptional changes was conducted using bulk-tissue generated RNA-seq data from microdissected cortices and hippocampi as a function of aging, which can be explored at the UCI Mouse Explorer and AD Knowledge Portal. This deep-phenotyping pipeline identified novel aspects of age-related pathology in the 5xFAD model.
2021-03-04 | GSE168137 | GEO
Project description:Spatial transcriptomics analysis was performed to detect differential gene expression in brain sections of of wild type, 5XFAD mice (model of Alzheimer's Disease), 5XFAD mice treated with either vehicle or human neural stem cells (hNSC)
2023-12-31 | GSE209583 | GEO
Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. There are two types of AMD: dry AMD and wet AMD. While laser-induced choroidal neovascularization has been used extensively in the studies of wet AMD by presenting the main features of human wet AMD, there was no established mouse model which fully recapitulates the cardinal features of human dry AMD. In this regard, lack of appropriate mouse model for dry AMD hampered the translational research on the pathogenesis and development of therapeutic agents. We recently suggested that 5XFAD mice could be a mouse model of dry AMD with regard to the amyloid beta (Aβ) related pathology. In this study, using transmission electron microscope, we analyzed ultrastructure of retinal pigment epithelium (RPE) of 5XFAD mice. Of importance, aged 5XFAD mice had ultrastructural changes of RPE and Bruchâs membrane compatible with cardinal features of dry AMD, including loss of apical microvilli and basal infolding of RPE, increased thickness of Bruchâs membrane, basal laminar and linear deposits, and accumulation of lipofuscin granules and undigested photoreceptor outer segment-laiden phagosomes. Using a threshold of 1.2 fold difference, we found â564â differentially expressed genes of which â190â were up-regulated and â374â were down-regulated in the RPE complex of aged 5XFAD mice. These altered genes were implicated in the pathogenesis of AMD including inflammation and immune response-related genes and retinol metabolism-related genes. Taken together, we suggest that aged 5XFAD mice can be used for dry AMD mouse model. All 5XFAD mice used were heterozygotes with respect to the transgene, and non-transgenic wild-type littermate (WT) mice served as controls.
2016-08-10 | E-GEOD-85408 | biostudies-arrayexpress
Project description:Transcriptome profiles of wild-type, IRF8KO, IRF8cKO, Batf3KO, 5xFAD, and 5xFAD/IRF8KO microglia [RNA-seq]
| PRJNA964778 | ENA
Project description:The role of the lineage-determining transcription factor IRF8 in microglia remains unelucidated. We report the genome-wide, transcriptome profiles of wild-type, IRF8KO, IRF8cKO, Batf3KO, 5xFAD, and 5xFAD/IRF8KO microglia. Deep-sequencing and subsequent differential analysis revealed the impacts of IRF8 on microglia-specific transcription programs, such as cell identity. Sall1 and Batf3 genes were identified as a downstream transcription factor of IRF8, and Batf3 dependent genes showed correlation with IRF8-dependent genes in microglia. The conditional depletion of IRF8 gene after microglial maturation (P14) increased or decreased the gene expression, most of which were shared with those of IRF8KO. This study provides a novel insight into understanding transcriptional programs in microglia.
2023-06-01 | GSE231403 | GEO
Project description:Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, how this metabolic interplay may be affected during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in hippocampal brain slices of 5xFAD mice. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, cerebral cortical slices of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. When we explored the brain proteome and metabolome of the 5xFAD mice, we found limited changes, supporting that the functional metabolic disturbances between neurons and astrocytes are early events in AD pathology. In addition, we show that synaptic mitochondrial and glycolytic function was impaired selectively in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex region and cell specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.
2021-11-09 | PXD025240 | Pride
Project description:Physical activity is considered a promising preventive intervention to reduce the risk of developing Alzheimer’s disease (AD). However, the positive effect of exercise therapy has not been proven conclusively yet, likely due to confounding factors such as varying activity regimens and life or disease stages. To examine the impact of different exercise regimens in the early disease stages, we subjected young 5xFAD and wild-type mice to 1-day (acute, 3-month-old) and 30-day (chronic, 2-month-old) voluntary wheel running and compared them with age-matched sedentary controls. We observed a significant increase in brain lactate levels in acutely trained 5xFAD mice relative to all other experimental groups. Subsequent RNA-seq analysis from brain did not reveal major differences in transcriptomic regulation between training durations in 5xFAD mice. In contrast, acute training yielded large gene expression differences in wild-type animals relative to their chronically trained and sedentary counterparts. The comparison of 5xFAD and wild-type mice showed the highest transcriptional differences in the chronic and sedentary groups, whereas acute training was associated with much fewer DEGs. In conclusion, our results suggest that different training durations did not affect the global transcriptome of 3-month-old 5xFAD mice, whereas acute running seemed to induce a similar transcriptional stress state in wild-type animals as already known for 5xFAD mice.
2021-01-14 | GSE164798 | GEO
Project description:Goals: 1) To analyse amyloid-b aggregation and proteomic and transcriptomic changes in 2, 5 and 8 months old 5xFAD mice 2) To determine differentially expressed proteins correlating and anti-correlating with aggregate formation 3) To analyse whether correlating or anti-correlating proteins change at transcriptional or posttranscriptional level 4) To determine differentially expressed or correlating and anti-correlating proteins which overlap with proteomic changes found in human AD brains 5) To analyse, whether Arl8b, which is an Ab aggregate correlating protein, show significant changes in CSF of AD patients Summary: Our study revealed that Ab42 driven aggregate formation leads to distinct brain region-specific proteome changes in 5xFAD mouse brains. We detected 195 dysregulated proteins correlating or anti-correlating with Ab-aggregation in hippocampus and cortex of 5xFAD mice. Most of these protein changes were caused by posttranscriptional mechanisms, only a minor part was associated with transcriptional dysregulation. A fraction of the Ab-correlated and anti-correlated DEPs was conserved in post-mortem brains of AD patients revealing that proteome changes in 5xFAD mice recapitulate disease-relevant changes in AD patient brains. Among the group of Ab42-correlating proteins, we have found the lysosome associated protein Arl8b, which is present in increased levels in CSF samples of AD patients and might have potential as an AD biomarker.
2023-03-01 | GSE198226 | GEO