Systematic Phenotyping and Characterization of the 5xFAD mouse model of Alzheimer’s Disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA706199 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13842700_1.fastq.gz | Fastqsanger.gz | |||
| SRR13842700_2.fastq.gz | Fastqsanger.gz | |||
| SRR13842800_1.fastq.gz | Fastqsanger.gz | |||
| SRR13842800_2.fastq.gz | Fastqsanger.gz | |||
| SRR13842701_1.fastq.gz | Fastqsanger.gz |
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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.
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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:Mouse models of human diseases are invaluable tools for studying pathogenic mechanisms and testing interventions and therapeutics. For disorders such as Alzheimer's disease in which numerous models are being generated, a challenging first step is to identify the most appropriate model and age to effectively evaluate new therapeutic approaches. Here we conducted a detailed phenotypic characterization of the 5xFAD model on a congenic C57BL/6 J 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 MODEL-AD Explorer and AD Knowledge Portal. This deep-phenotyping pipeline identified novel aspects of age-related pathology in the 5xFAD model.
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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.
2013-09-10 | GSE50521 | 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.
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Project description:It was recently revealed that gut microbiota promote amyloid-beta (Aβ) burden in mouse models of Alzheimer’s disease (AD). However, the underlying mechanisms when using either germ-free (GF) housing conditions or treatments with antibiotics (ABX) remained unknown. In this study, we show that GF and ABX-treated 5x familial AD (5xFAD) mice developed attenuated hippocampal Aβ pathology and associated neuronal loss, and thereby delayed disease-related memory deficits. While Ab production remained unaffected in both GF and ABX-treated 5xFAD mice, we noticed in GF 5xFAD mice enhanced microglial Aβ uptake at early stages of the disease compared to ABX-treated 5xFAD mice. Furthermore, RNA-sequencing of hippocampal microglia from SPF, GF and ABX-treated 5xFAD mice revealed distinct microbiota-dependent gene expression profiles associated with phagocytosis and altered microglial activation states. Taken together, we observed that constitutive or induced microbiota modulation in 5xFAD mice differentially controls microglial Aβ clearance mechanisms preventing neurodegeneration and cognitive deficits.
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Project description:Pantethine, an anti-cholesterol drug, was shown to inhibit the Ab (amyloid beta) peptide-induced expression of IL-1b in primary culture astrocytes derived from either untreated Ab-treated and untreated 5XFAD or Ab-treated WT. These observations prompted us to investigate the effects of pantethine at the transcriptomic level in the mouse AD model.
2018-07-15 | E-MTAB-6772 | biostudies-arrayexpress
Project description:To investigate the potential noninvasive early biomarkers of AD in 5XFAD mouse model, we investigate the proteome of urinary exosomes present in 1-month-old (before amyloid-β accumulation) 5XFAD mouse models and their littermate controls. Another two groups of 2 and 6 months-old urinary samples were collected for monitoring the dynamic change of target proteins during AD progression.
2021-01-04 | PXD021935 | Pride
Project description:Mouse models of Alzheimer’s Disease (AD), which show progression through various AD stages reflective of human pathology, like 5XFAD, are well established tools for uncovering novel AD related pathways. In addition, they permit temporal examination of the intermingling of AD related pathways and can be used to potentially dissect initiating and propagating events in AD, which are critical for developing biomarkers or designing interventions in early stages of the disease. The present research offers a robust and exhaustive tandem MS examination of a familial AD mice model with a design including variables of: time (three, six, and nine months), genetic background (5XFAD vs. WT), and sex (equal males and females).
2022-09-16 | PXD030161 | Pride
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.
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