RNA-Seq of human primary microglial cells treated with vehicle or human paired helical filaments (PHFs) purified from human tauopathy autopsy brain
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 4000
ORGANISM(S): Homo sapiens
SUBMITTER: Shanya Jiang
PROVIDER: E-MTAB-5742 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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2023-03-01 | GSE221856 | GEO
Project description:Alzheimer's Disease (AD) is a devastating neurodegenerative disorder affecting approximately 4 million people in the U.S. alone. AD is characterized by the presence of senile plaques and neurofibrillary tangles in cortical regions of the brain. These pathological markers are thought to be responsible for the massive cortical neurodegeneration and concomitant loss of memory, reasoning, and often aberrant behaviors that are seen in patients with AD. Understanding the molecular mechanisms whereby these histopathological markers develop will greatly enhance our understanding of AD development and progression. A clearer understanding of the mechanisms underlying neurofibrillary tangle formation specifically may help to clarify the basis for dementia of AD as well as the dementias associated with other diseases that are collectively referred to as "tauopathies."; To expression profile both neurons containing neurofibrillary tangles and normal neurons from the entorhinal cortex of 10 mid-stage AD cases. The gene expression profile of neurons that contain neurofibrillary tangles will differ from the expression profile of histopathologically normal neurons from the same patient and from the same brain region. Some of these differences will be informative as to the mechanisms of tangle formation. Experiment Overall Design: First use laser capture microdissection to select 1000 neurons bearing neurofibrillary tangles and 1000 normal neurons from the layer 2 stellate island neurons of the entorhinal cortex of 10 mid-stage AD cases. Second, to isolate the RNA from these captured neurons, perform double round linear amplification and hybridize the labeled cRNA to affymetrix U133A arrays. Third, to use paired, permutational t-tests to analyze the microarray data to select tangle-specific differences in gene expression. For the purposes of submitting this proposal, a value of 1 ug of RNA was entered due to web site constraints on values placed in that field. However, all samples are from LCM captured cells and the actual RNA yield is likely closer to 100 pg.
2009-09-05 | E-GEOD-4757 | biostudies-arrayexpress
Project description:One of the defining pathological features of Alzheimer’s Disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible tau kinases attractive therapeutic targets. The full complement of tau interacting kinases in AD brain and their activity in disease remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in human AD, familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W & P301L) and corticobasal degeneration (CBD) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activation in both AD and FTDP-17 and map TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activation may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.
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Project description:Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles in addition to neuroinflammation and changes in brain lipid metabolism. Recent findings have demonstrated that microglia are key drivers of neurodegeneration in tauopathy mouse models. A subset of microglia referred to as disease-associated microglia (DAM) display gene signatures signifying changes in proinflammatory signaling and lipid metabolism in mouse models of amyloid and tau pathology. Ch25h is a DAM gene encoding cholesterol 25-hydroxylase that produces 25-hydroxycholesterol (25HC), a known modulator of inflammation as well as lipid metabolism. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and 25HC there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory cytokine and chemokine signaling in microglia and restored sterol synthesis. Our results suggest a key role for Ch25h/25HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases.
2023-12-08 | GSE242896 | GEO
Project description:Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-b and intraneuronal hyperphosphorylated, tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-b and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-b plaques or both amyloid-b plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-b load and localized to amyloid-b plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with over tau pathology. This full characterization of human disease associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
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Project description:Alzheimer's Disease (AD) is a devastating neurodegenerative disorder affecting approximately 4 million people in the U.S. alone. AD is characterized by the presence of senile plaques and neurofibrillary tangles in cortical regions of the brain. These pathological markers are thought to be responsible for the massive cortical neurodegeneration and concomitant loss of memory, reasoning, and often aberrant behaviors that are seen in patients with AD. Understanding the molecular mechanisms whereby these histopathological markers develop will greatly enhance our understanding of AD development and progression. A clearer understanding of the mechanisms underlying neurofibrillary tangle formation specifically may help to clarify the basis for dementia of AD as well as the dementias associated with other diseases that are collectively referred to as "tauopathies." To expression profile both neurons containing neurofibrillary tangles and normal neurons from the entorhinal cortex of 10 mid-stage AD cases. The gene expression profile of neurons that contain neurofibrillary tangles will differ from the expression profile of histopathologically normal neurons from the same patient and from the same brain region. Some of these differences will be informative as to the mechanisms of tangle formation. Keywords: disease-state analysis
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