Identifying blood transcriptome biomarkers of Alzheimer’s disease using transgenic mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE144459 | GEO | 2020/08/23
REPOSITORIES: GEO
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Project description:Identifying blood transcriptome biomarkers of Alzheimer’s disease using transgenic mice
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Project description:The 3xTg-AD mouse is a widely used model in the study of Alzheimer’s Disease (AD). It has been extensively characterized both from the anatomical and behavioral point of view but poorly studied at the transcriptomic level. For the first time, this study characterizes the whole blood transcriptome of the 3xTg-AD mouse at three and six months of age and evaluates how gene expression is modulated by transcranial direct current stimulation (tDCS). RNA-seq analysis revealed 183 differentially expressed genes (DEGs) that were a direct signature of the genetic background of the mouse. The expression profile of age-related genes in the 3 months-old 3xTg-AD mice was more similar to that of 6 months rather than 3 months-control mice, suggesting a premature aging of the 3xTg-AD mice. Moreover, in the 6 months-old 3xTg-AD mice, we observed a high number of DEGs that could represent good peripheral biomarkers of AD progression. Finally, tDCS was associated with gene expression changes in the 3xTg-AD but not in the control mice. In conclusion, this study provides a better molecular characterization of the 3xTg-AD mouse and suggests that blood gene expression can be used to identify new biomarkers of AD progression and treatments effect.
2021-07-19 | GSE178662 | GEO
Project description:The abnormal regulation of amyloid-b (Ab) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimer’s disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Ab deposition and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Ab metabolism, including Tau, Mapk, and Sirt1.
2016-07-17 | GSE84481 | GEO
Project description:Early- and late-onset forms of Alzheimer’s disease (AD) share common features that include abnormalities in lipid metabolism, immune response and synaptic function. Of these, the role of lipids remains the least understood. Our study revealed that molecular functions related to Stearoyl-CoA Desaturase (SCD), the rate limiting enzyme in monounsaturated fatty acid synthesis were specifically altered in the hippocampus of 3xTg-AD (a model of early-onset AD). Remarkably, infusion of an SCD inhibitor (SCDi) reversed 40% of altered immune and synapse genes, rescue dendritic spine number and structure, recovered activity-associated immediate-early gene expression and restored learning and memory in 3xTg-AD mice. In addition, we employed single cell RNA sequencing to characterize the cellular landscape of microglia subpopulations within the 3xTg hippocampus and uncovered that SCDi reversed microglial activation and polarization. Together, we show that a single lipid enzyme, SCD, impinges on the core features of AD.
2022-02-25 | GSE167600 | GEO
Project description:Early- and late-onset forms of Alzheimer’s disease (AD) share common features that include abnormalities in lipid metabolism, immune response and synaptic function. Of these, the role of lipids remains the least understood. Our study revealed that molecular functions related to Stearoyl-CoA Desaturase (SCD), the rate limiting enzyme in monounsaturated fatty acid synthesis were specifically altered in the hippocampus of 3xTg-AD (a model of early-onset AD). Remarkably, infusion of an SCD inhibitor (SCDi) reversed 40% of altered immune and synapse genes, rescue dendritic spine number and structure, recovered activity-associated immediate-early gene expression and restored learning and memory in 3xTg-AD mice. In addition, we employed single cell RNA sequencing to characterize the cellular landscape of microglia subpopulations within the 3xTg hippocampus and uncovered that SCDi reversed microglial activation and polarization. Together, we show that a single lipid enzyme, SCD, impinges on the core features of AD.
2022-02-25 | GSE167601 | GEO
Project description:Alzheimer’s dementia (AD) is the most common form of dementia and without readily available clinical biomarkers. Blood-derived proteins are routinely used for diagnostics, however, comprehensive plasma profiling is challenging due to the large dynamic range in protein concentrations. Extracellular vesicles (EVs) can cross the blood-brain barrier and may provide a source for AD related biomarkers. We investigated plasma-derived EV proteins for biomarkers towards AD diagnostics from 10 AD patients, 10 Mild Cognitive Impairment (MCI) patients, and 9 healthy controls (Con) using liquid chromatography - tandem mass spectrometry (LC-MS/MS). EV enrichment was performed using a double centrifugation of 100,000 × g, 1h, 4°C with a wash of the pellet. Some AD patients presented with highly elevated FXIIIA1 (log2 FC: 4.6, p-value: 0.005) and FXIIIB (log2 FC: 4.9, p-value: 0.018). A group of proteins was identified discriminating Con and AD (AUC: 0.91, CI: 0.67-1.00) with ORM2 (AUC: 1.00, CI: 1.00-1.00), RBP4 (AUC: 0.99, CI: 0.95-1.00), and HYDIN (AUC: 0.89, CI: 0.72-1.00) found especially relevant for AD. This indicates that EVs provide an easily accessible matrix for possible biomarkers for AD. Some of the MCI patients, with similar protein profiles as the AD group progressed to AD within a 2-year timespan.
2022-02-16 | PXD024216 | Pride
Project description:Alzheimer's disease (AD) was attributed to alterations in multiple epigenetic systems including DNA methylation and demethylation patterns. DNA 5-hydroxymethylcytosin (5hmC), an epigenetic hallmark, plays importantly regulatory role in many biological processes. However, the 5hmC-mediated epigenetic underpinnings of AD neurodegeneration remain poorly understood. Here we report that selective loss of 5hmC is substantially presented in human AD and 3xTg-AD mouse neocortical and hippocampal neurons. Quantitative genome-wide analysis of hMeDIP-seq reveals that neuron-specific shift in decreased 5hmC enrichment in regions of promoter, intergenic and gene body of mRNA and lncRNA genes was found in3xTg-AD mice. We further identified that TET3, an enzyme that converts 5-methylcytosine (5mC) to 5hmC, responded to Beta amyloid neuronal toxicity and was mainly responsible for loss of 5hmC in AD brain. Overexpression of human TET3 catalytic domain (hTET3CD) significantly improves the neuroinflammation, neuropathological progression and cognitive deficits in 3xTg-AD mice. These findings implicate as a potential hallmark, TET3-mediated 5hmC epigenetic dysregulation is involved in driving AD neurodegeneration.
2019-02-19 | GSE126713 | GEO
Project description:Human plasma samples from CDR = 0 and CDR ≥ 0.5 patients, and serum samples from non-diseased, non-surgical controls were probed onto human protein microarrays to test the utility of a previously established panel of MCI-specific autoantibody (aAB) biomarkers to detect prodromal AD presurgically in individuals admitted into the hospital for hip fracture repair (HFR) surgery.
2020-04-14 | GSE137422 | GEO
Project description:This manuscript describes methodology for the meta-analysis of published proteomics datasets from multiple publications to mine for cerebrospinal fluid (CSF)-based diagnostic biomarkers for Alzheimer’s disease (AD).The identified biomarkers are then validated in an independent cohort analyzed in house and two additional published large datasets. Specifically, the published data was mined from 6 independent and a 7th in-house acquired CSF proteomic datasets resulting in a meta-cohort with 73 AD cases and 77 controls. In-depth data analysis revealed 35 CSF biomarker candidates, many of which are associated with brain glucose homeostasis, which is described to be dysregulated in AD. Next, the list of identified biomarker candidates were then validated in a 2-pronged approach using i) an independent cohort analyzed in house, and ii) two recently published independent large scale datasets comprising in total more than 500 samples. The resulting biomarker panel consisting of three glycolytic enzymes was found to discriminate AD from controls. To our knowledge, this is the first study that described the mining and systematic re-analysis of previously published liquid chromatography mass spectrometry-based proteomics data to identify and validate biomarkers in general and CSF biomarkers for AD in particular. While the presented study focused on AD, the presented workflow can be applied to any disease for which published datasets are available.
2023-02-16 | PXD022649 | Pride
Project description:The abnormal regulation of amyloid-b (Ab) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimerâs disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Ab deposition and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Ab metabolism, including Tau, Mapk, and Sirt1. We used RNA-Seq to analyse the hippocampus of 3xTg-AD mice lacking the miR-132/212 cluster as well as Neuro2a cells overexpressing miR-132 mimics.
2016-07-17 | E-GEOD-84481 | biostudies-arrayexpress