4001db8d-4d95-4345-b076-968977979fe1 - samples
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ABSTRACT:
PROVIDER: EGAD00001008660 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Iron accumulation in microglia has been observed in Alzheimer’s disease and other neurodegenerative disorders and is thought to contribute to disease progression through various mechanisms including neuroinflammation. To study the interaction between iron accumulation and inflammation, we treated human induced pluripotent stem cell-derived microglia (iPSC-MG) with an increasing concentration of iron, in combination with inflammatory stimuli such as interferon gamma and amyloid β, and performed RNA sequencing.
| EGAS00001006112 | EGA
Project description:Plaques consisting of amyloid-β (Aβ) in the brain are characteristic for patients with Alzheimer´s disease. Aβ is enzymatically generated of the amyloid precursor protein. Furthermore, neprilysin, an Aβ-degrading enzyme, and its main activator the neuropeptide somatostatin (SST) are downregulated in Alzheimer´s disease. In the fusion protein SST-scFv8D3, SST is recombinantly fused to a blood-brain barrier transporter. The aim of this study was to study the effect of SST-scFv8D3 on the proteome of different brain regions in order to elucidate the anti-Alzheimer´s disease effects of this construct. SST-scFv8D3 and phosphate buffered saline (PBS) respectively were injected into transgenic mice of an Alzheimer´s disease model with the Swedish mutation (AβPP KM670/671NL) every 36 hours (three times in total). Homogenates of the hippocampus, the cerebellum and the rest of the cerebrum were lysed. Afterwards, filter aided tryptic digestion was performed. The resulting peptides were analyzed using LC-UDMSE. The data was searched against a randomized mouse database and label-free quantification analysis was done. In total 1869 proteins were found. Only the proteome of the hippocampus was affected by the treatment with SST-scFv8D3. 55 proteins were significantly up and 105 down regulated compared to the PBS treated mice. Among these were mitochondrial and synaptic proteins as well as some involved in neuron´s development indicating anti-Alzheimer disease effects of SST-scFv8D3 and supporting the future use of SST-scFv8D3 as a treatment option.
2021-06-28 | PXD022221 | Pride
Project description:Olfactory dysfunction manifests early in several neurodegenerative disorders. Olfaction is orchestrated by olfactory mucosal cells located in the upper nasal cavity. However, it is unclear how this tissue reflects key neurodegenerative features in Alzheimer’s disease. Here we report that Alzheimer´s disease olfactory mucosal cells secrete toxic amyloid-beta. We detail cell-type-specific gene expression patterns, unveiling 147 differentially expressed disease-associated genes compared to the cognitively healthy controls, and 5 distinct populations in globose basal cell -, myofibroblast-, and fibroblast/ stromal – like cells in vitro. Overall, coordinated alteration of RNA and protein metabolism, inflammatory processes and signal transduction were observed in multiple cell populations, suggesting a key role in pathophysiology. Our results demonstrate the potential of olfactory cell cultures in modelling Alzheimer´s disease. Moreover, for the first time we provide single cell data on olfactory mucosa in Alzheimer´s disease for investigating molecular and cellular mechanisms associated with the disease.
| EGAS00001006019 | EGA
Project description:Microarray analysis on human neuroblastoma cells exposed to iron, B-amyloid or the B-amyloid iron complex. Alzheimer's disease is associated with an abnormal accumulation of certain metal ions.
2019-05-15 | GSE40974 | GEO
Project description:Extracellular amyloid-β (Aβ) deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles (NFT) are two of the characteristic hallmarks in Alzheimer’s disease (AD). The regional progression of brain atrophy in AD highly correlates with tau accumulation but not amyloid deposition and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. To date, little is known about the extent or role of the adaptive immune response in the presence of Aβ or tau pathology. We systematically compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not amyloid, developed a unique innate and adaptive immune response and that depletion of microglia or T-cells blocked tau-mediated neurodegeneration. T cells, especially cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of IFN-γ and PD-1signaling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in AD and primary tauopathies.
2023-03-01 | GSE221856 | GEO
Project description:γ-Secretase is involved in the regulated intramembrane proteolysis (RIP) of a variety of integral membrane proteins and generates the amyloid peptide (Aβ) in Alzheimer’s Disease (AD). Microglia are centrally involved in AD, but the substrates and function of γ-secretase in these cells remain largely unstudied. Using a novel γ-Secretase Substrate Identification (G-SECSI) method, we identified 85 substrates, of which 59 were previously unknown, in stem cell derived microglia-like cells. More than 60% of those are signalling receptors possibly involved in cell state regulation. Inhibition of γ-secretase using Semagacestat or selective genetic knockout alters the expression of homeostatic (HM) and disease-associated (DAM) genes, in particular when microglia are exposed to amyloid plaques in vivo. Thus, γ-secretase regulates tonic signaling via a spectrum of substrates in microglia in steady state, and its blockage results in the defective transition to the DAM response in AD.
2023-11-14 | PXD039238 | Pride
Project description:PLCγ2-P522R (phospholipase C gamma 2, proline 522 to arginine) is a protective variant that reduces the risk for late onset Alzheimer’s disease (LOAD). Recently, it was shown to decrease β-amyloid pathology in 5XFAD mouse model of AD. In this study, our goal was to investigate the protective functions of PLCγ2-P522R variant in less aggressive mouse model of AD as well as to assess underlying mechanisms at the molecular and cellular level using mouse and human microglia models. The effects of the protective PLCγ2-P522R variant on microglia activation, AD-related β-amyloid and neuronal pathologies, as well as behavioral changes were investigated in PLCγ2-P522R knock-in mice crossbred with an APP/PS1 mouse model of AD. Transcriptomic, proteomic, and functional studies were carried out in cultured and acutely isolated adult PLCγ2-P522R mouse microglia to study molecular mechanisms. Finally, microglia-like cell models generated from blood and skin biopsy samples of the PLCγ2-P522R variant carriers were employed to translate the key findings in human cells. Our results demonstrate that the PLCγ2-P522R variant reduces brain β-amyloid plaque burden of APP/PS1 mice. Simultaneously, PLCγ2-P522R variant increased non-proinflammatory microglia activation and microglia clustering around β-amyloid plaques, leading to reduced β-amyloid plaque-associated neuronal dystrophy. In cultured mouse primary microglia, PLCγ2-P522R variant decreased accumulation of large lipid droplets, reduced cell stress, and increased acute response to strong inflammatory stimuli. Transcriptomic and proteomic analyses in acutely isolated adult mouse microglia as well as in human monocyte-derived microglial cells showed that PLCγ2-P522R upregulates mitochondrial fatty acid oxidation and downregulates inflammatory/interferon signaling pathways. Accordingly, PLCγ2-P522R increased mitochondrial respiration in iPSC -derived microglial cells. Together, these findings suggest that PLCγ2-P522R variant exerts protection against AD-associated β-amyloid and neuronal pathologies via enhancing microglial barrier formation around β-amyloid plaques, but suppressing pro-inflammatory activation. Observed changes in fatty acid metabolism and mitochondrial flexibility as well as the downregulation of genes involved in inflammatory signaling pathways suggest that these protective effects of the PLCγ2-P522R variant are mediated through an anti-ageing mechanism.
2024-09-16 | GSE277167 | GEO
Project description:Microglia become activated by disturbances in the homeostasis of their local microenvironment. While there are varying degrees of microglia activation, a pro-inflammatory reactive state induced by exposure to stimuli like LPS and IFN-γ. In this study, we identified a total of 5497 proteins in whole cell proteome and 4938 proteins for secretome of activated BV-2 mouse microglia cell line with LPS or IFN-γ using improved shotgun proteomic approach. From the differentially expressed proteins in stimulated microglia, we were able to classify pathways related immune-inflammatory response or metabolism. Moreover, we performed longitudinal quantification of secreted proteins during the detrimental activation of microglia which releases neurotoxic molecules mediated neuronal cell loss in the brain region.
2017-08-09 | PXD006558 | Pride
Project description:Puri2010 - Mathematical Modeling for the
Pathogenesis of Alzheimer's Disease
Puri2010 - Mathematical Modeling for the Pathogenesis of
Alzheimer's Disease
Encoded non-curated model. Issues:
- Confusing replacement of
α16
when t = 3 years
- Confusing 4th rate equation
This model is described in the article:
Mathematical modeling for
the pathogenesis of Alzheimer's disease.
Puri IK, Li L.
PLoS ONE 2010; 5(12): e15176
Abstract:
Despite extensive research, the pathogenesis of
neurodegenerative Alzheimer's disease (AD) still eludes our
comprehension. This is largely due to complex and dynamic
cross-talks that occur among multiple cell types throughout the
aging process. We present a mathematical model that helps
define critical components of AD pathogenesis based on
differential rate equations that represent the known
cross-talks involving microglia, astroglia, neurons, and
amyloid-? (A?). We demonstrate that the inflammatory activation
of microglia serves as a key node for progressive
neurodegeneration. Our analysis reveals that targeting
microglia may hold potential promise in the prevention and
treatment of AD.
This model is hosted on
BioModels Database
and identified by:
MODEL1409240001.
To cite BioModels Database, please use:
BioModels Database:
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quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2015-04-15 | MODEL1409240001 | BioModels
Project description:Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n=11) and control brain (n=14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.
2023-07-09 | GSE236268 | GEO