Evaluation of animal models of AD
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA408065 | ENA |
REPOSITORIES: ENA
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Project description:This study was designed to measure expressional profile of genes from brain tissues of animal models of AD.
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Project description:Characterizing the detergent insoluble brain proteome of sporadic late-onset Alzheimer’s disease (LOAD) has identified proteins and pathways associated with disease pathogenesis. Similar studies in early onset Alzheimer’s disease cases due to presenilin-1 mutations (PS1-EOAD), along with more detailed correlations with insoluble proteomes from LOAD and AD transgenic rodents, are limited. We therefore utilized quantitative proteomics to identify proteins that were significantly changing in the PS1-EOAD insoluble proteome versus controls. Comparison with the LOAD insoluble proteome identified common pathologic AD markers in addition to unique PS1-EOAD insoluble proteins. Similarly, weighted correlation network analysis (WGCNA) identified PS1-EOAD and LOAD co-expression modules with both like and disparate expression levels. Finally, we compared the human PS1-EOAD insoluble proteome to transgenic AD mouse and rat insoluble proteomes to understand how well these models mimic the human disease. Although many common AD pathologic findings were found in the rodents, there were multiple PS1-EOAD proteome changes not well recapitulated in the animal models. These proteomic studies highlight unique PS1-EOAD proteome changes as compared to LOAD and identify limitations to using AD transgenic rodents to study some aspects of AD.
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Project description:Animal models of neurodevelopmental disorders treated with TAK-418
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Project description:The relationship between repetitive mild traumatic brain injury (r-mTBI) and Alzheimer’s disease (AD) is well-recognized. However, the precise nature of how r-mTBI leads to or precipitates AD pathogenesis is currently not understood. Part A: Plasma biomarkers potentially provide non-invasive tools for detecting neurological changes in the brain, and can reveal overlaps between long-term consequences of r-mTBI and AD. In this study we address this by generating time-dependent molecular profiles of response to r-mTBI and AD pathogenesis in mouse models using unbiased proteomic analyses. To model AD, we used the well-validated hTau and PSAPP(APP/PS1) mouse models that develop age-related tau and amyloid pathological features respectively, and our well-established model of r-mTBI in C57BL/6 mice. Plasma were collected at different ages (3, 9, and 15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes, or at different timepoints after r-mTBI (24hrs, 3, 6, 9 and 12 months post-injury). Liquid chromatography/mass spectrometry (LC-MS) approaches coupled with Tandem Mass Tag labeling technology were applied to develop molecular profiles of protein species that were significantly differentially expressed as a consequence of mTBI or AD. Mixed model ANOVA after Benjamini-Hochberg correction, and a stringent cut-off identified 31 proteins significantly changing in r-mTBI groups over time and, when compared with changes over time in sham mice, 13 of these were unique to the injured mice. The canonical pathways predicted to be modulated by these changes were LXR/RXR activation, production of nitric oxide and reactive oxygen species and complement systems. We identified 18 proteins significantly changing in PSAPP mice and 19 proteins in hTau mice compared to their wildtype littermates with ageing. Six proteins were found to be significantly regulated in all three models i.e. r-mTBI, hTau and PSAPP mice compared to their controls. The top canonical pathways coincidently changing in all three models were LXR/RXR activation, and production of nitric oxide and reactive oxygen species. This work suggests potential biomarkers for TBI and AD pathogenesis and for the overlap between these two, and warrant targeted investigation in human populations. Part B: In this part of the study we address the above problem by utilizing our unbiased proteomic approach to generate detailed time-dependent brain molecular profiles of response to repetitive mTBI and AD pathogenesis in established mouse models. The same animal models described above were used herein. A LC/MS approach coupled with TMT labeling was also employed. Results: Mixed model ANOVA after Benjamin Hochberg correction identified 30 and 47 proteins that were specifically unique and changing in the hippocampus and cortex, respectively, within the r-mTBI group alone when compared with changes overtime in sham mice. PI3K/AKT signaling, Protein Kinase A signaling and PPAR/RXR activation in the hippocampus, and Protein Kinase A signaling, GNRH signaling and B cell receptor signaling in the cortex were the top canonical systems significantly altered in injury groups compared to sham mice. Mixed model AONVA identified 19 proteins significantly changing in the cortex of PSAPP mice and 7 proteins in hTau mice compared to their relative wildtype littermates respectively. In addition to the heterogeneous changes observed in the TBI and AD mouse models, there was a notable convergence and coincidental change in 6 unique proteins identified in the repetitive mTBI model and the hTau and PSAPP model. These proteins ostensibly indicate significant common pathobiological responses involving alterations in mitochondrial bioenergetics and energy metabolism, aberrant cytoskeletal reorganization and alterations in intracellular signaling transduction cascades. Conclusion: We believe that this work could help identify the common molecular substrates responsible for the precipitation of AD pathogenesis following repetitive mTBI, and also help to identify novel biological targets for therapeutic modulation in mTBI and AD.
2019-01-11 | PXD010664 | Pride
Project description:We report the histone modification profiles in the brain cortex of animal models of neurodevelopmental disorders (rat with prenatal exposure to valproate and mouse with prenatal exposure to poly I:C) treated with TAK-418.
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Project description:The relationship between repetitive mild traumatic brain injury (r-mTBI) and Alzheimer’s disease (AD) is well-recognized. However, the precise nature of how r-mTBI leads to or precipitates AD pathogenesis is currently not understood. Part A: Plasma biomarkers potentially provide non-invasive tools for detecting neurological changes in the brain, and can reveal overlaps between long-term consequences of r-mTBI and AD. In this study we address this by generating time-dependent molecular profiles of response to r-mTBI and AD pathogenesis in mouse models using unbiased proteomic analyses. To model AD, we used the well-validated hTau and PSAPP(APP/PS1) mouse models that develop age-related tau and amyloid pathological features respectively, and our well-established model of r-mTBI in C57BL/6 mice. Plasma were collected at different ages (3, 9, and 15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes, or at different timepoints after r-mTBI (24hrs, 3, 6, 9 and 12 months post-injury). Liquid chromatography/mass spectrometry (LC-MS) approaches coupled with Tandem Mass Tag labeling technology were applied to develop molecular profiles of protein species that were significantly differentially expressed as a consequence of mTBI or AD. Mixed model ANOVA after Benjamini-Hochberg correction, and a stringent cut-off identified 31 proteins significantly changing in r-mTBI groups over time and, when compared with changes over time in sham mice, 13 of these were unique to the injured mice. The canonical pathways predicted to be modulated by these changes were LXR/RXR activation, production of nitric oxide and reactive oxygen species and complement systems. We identified 18 proteins significantly changing in PSAPP mice and 19 proteins in hTau mice compared to their wildtype littermates with ageing. Six proteins were found to be significantly regulated in all three models i.e. r-mTBI, hTau and PSAPP mice compared to their controls. The top canonical pathways coincidently changing in all three models were LXR/RXR activation, and production of nitric oxide and reactive oxygen species. This work suggests potential biomarkers for TBI and AD pathogenesis and for the overlap between these two, and warrant targeted investigation in human populations. Part B: In this study we also address the aformention gap in the field by utilizing our unbiased proteomic approach to generate detailed time-dependent brain molecular profiles of response to repetitive mTBI and AD pathogenesis in established mouse models. Methods: We used the well-validated hTau and PSAPP(APP/PS1) mouse models that develops age-related tau and amyloid pathological features respectively, and our well-established model of repetitive-mTBI in C57BL/6 mice. Brain tissue from these animals were collected at different time points after repetitive mTBI (24hrs -12 months post-injury) and at different ages (3-15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes previously described in all models. Liquid chromatography/mass spectrometry (LC-MS) approach coupled with Tandem Mass Tag labeling technology were applied to reveal molecular profiles of proteins and pathways that are significantly altered as a consequence of AD or repetitive mTBI. Results: Mixed model ANOVA after Benjamin Hochberg correction identified 30 and 47 proteins that were specifically unique and changing in the hippocampus and cortex, respectively, within the r-mTBI group alone when compared with changes overtime in sham mice. PI3K/AKT signaling, Protein Kinase A signaling and PPAR/RXR activation in the hippocampus, and Protein Kinase A signaling, GNRH signaling and B cell receptor signaling in the cortex were the top canonical systems significantly altered in injury groups compared to sham mice. Mixed model AONVA identified 19 proteins significantly changing in the cortex of PSAPP mice and 7 proteins in hTau mice compared to their relative wildtype littermates respectively. In addition to the heterogeneous changes observed in the TBI and AD mouse models, there was a notable convergence and coincidental change in 6 unique proteins identified in the repetitive mTBI model and the hTau and PSAPP model. These proteins ostensibly indicate significant common pathobiological responses involving alterations in mitochondrial bioenergetics and energy metabolism, aberrant cytoskeletal reorganization and alterations in intracellular signaling transduction cascades. Conclusion: We believe that this work could help identify the common molecular substrates responsible for the precipitation of AD pathogenesis following repetitive mTBI, and also help to identify novel biological targets for therapeutic modulation in mTBI and AD.
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