Human Tau Mutations in Cerebral Organoids Induce a Progressive Dyshomeostasis of Cholesterol
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE208418 | GEO | 2022/07/21
REPOSITORIES: GEO
Similar Datasets
Project description:Human Tau Mutations in Cerebral Organoids Induce a Progressive Dyshomeostasis of Cholesterol
| PRJNA859858 | ENA
Project description:This is a simple and reproducible protocol in which the hCOs generated are homogeneous and develop properly presenting proliferative ventricular zones (VZs) formed by neural and radial glia (RG) precursors that differentiate to give rise to mature neurons and glia cells. The hCOs at four weeks of maturation present additional cell types such as oligodendrocyte precursors, astrocytes, microglia and endothelial cells as shown by single‐cell RNA sequencing (scRNA‐seq) and immunohistochemistry (IHC).
2023-10-01 | GSE242329 | GEO
Project description:Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer’s disease (AD) with APOE4 increasing and APOE2 decreasing risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared to ApoE3 or the absence of ApoE. However, the role of ApoE isoforms in regulating lipid metabolism in the setting of tauopathy is unknown. Here, by using targeted lipidomics coupled with histological analysis, we demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation along with significant perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via administration of the LXR agonist GW3965 reduces lipid droplet accumulation in primary E4 microglia in vitro and GW3965 or Abca1 overexpression strongly attenuates tau pathology, neurodegeneration, and synapse loss in P301S/ApoE4 mice. By immunostaining, bulk and snRNA sequencing, we demonstrate reductions in reactive astrocytes and microglia as well as significant changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids via Abca1 could serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.
2023-12-08 | GSE242693 | GEO
Project description:Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer’s disease (AD) with APOE4 increasing and APOE2 decreasing risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared to ApoE3 or the absence of ApoE. However, the role of ApoE isoforms in regulating lipid metabolism in the setting of tauopathy is unknown. Here, by using targeted lipidomics coupled with histological analysis, we demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation along with significant perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via administration of the LXR agonist GW3965 reduces lipid droplet accumulation in primary E4 microglia in vitro and GW3965 or Abca1 overexpression strongly attenuates tau pathology, neurodegeneration, and synapse loss in P301S/ApoE4 mice. By immunostaining, bulk and snRNA sequencing, we demonstrate reductions in reactive astrocytes and microglia as well as significant changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids via Abca1 could serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.
2023-12-08 | GSE242180 | GEO
Project description:Background: Iron trafficking and accumulation has been associated with Alzheimer’s disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterised, making it difficult to explore these in existing datasets. Results: We identified sets of genes predicted to contain Iron Responsive Elements (IREs), and used these to explore iron dyshomeostasis responses in transcript datasets involving (1) cultured cells under iron overload and deficiency treatments, (2) post-mortem brain tissues from AD and other neuropathologies, (3) 5XFAD transgenic mice modelling AD pathologies, and (4) a zebrafish knock-in model of early-onset, familial AD (fAD). IRE gene sets were sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, we see changes in 3’ IRE transcript abundance as amongst the earliest observable in zebrafish fAD-like brains and preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some 3’ IRE transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead show decreased stability, indicating that this is not a generalizable paradigm. Conclusions: Our results reveal iron dyshomeostasis as a likely early driver of fAD and as able to distinguish AD from other brain pathologies. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis responses in different species, tissues, and conditions.
2020-05-06 | GSE149149 | GEO
Project description:Progressive myoclonus epilepsy (PME) of Unverricht-Lundborg-type (EPM1) is an autosomal recessive neurodegenerative disorder with the highest incidence of PME worldwide. Mutations in the gene encoding cystatin B (CSTB) are the primary genetic cause of EPM1. Here, we investigate the role of CSTB during neurogenesis in vivo in the developing mouse brain and in vitro in human cerebral organoids (hCOs) derived from EPM1 patients. Remarkably, we find that CSTB (but not one of its pathological variants) is secreted into the mouse cerebral spinal fluid and the conditioned media from hCOs. In embryonic mouse brain, we find that functional CSTB influence progenitors’ proliferation and simultaneously modulate neuronal distribution by attracting interneurons to the site of secretion via cell non-autonomous mechanisms. Similarly, in patient-derived hCOs, low levels of functional CSTB result in an alteration of progenitor’s proliferation, premature differentiation, and changes in interneurons migration. Secretion and extracellular matrix organization are the biological processes particularly affected as revealed by proteomic analysis in patients’ hCOs. Overall, our data shed new light on the cellular mechanisms underlying the development of EPM1.
2020-05-13 | PXD018021 | Pride
Project description:Transcriptomic studies revealed that hundreds of mRNAs show differential expression in the brains of sleeping versus awake rats, mice, flies, and sparrows. Although these results have offered clues regarding the molecular consequences of sleep and sleep loss, their functional significance thus far has been limited. This is because the previous studies pooled transcripts from all brain cells, including neurons and glia. In the following experiment, we studied the specific effects of sleep and wake conditions on glia cells of mouse cerebral cortex using the genetically targeted translating ribosome affinity purification (TRAP) methodology. We used bacterial artificial chromosome (BAC) transgenic mice expressing EGFP tagged ribosomal protein L10a in astrocytes which constitute a defined cellular population of the mouse brain. Using this approach, we could extract only the astrocytic mRNAs, and only those already committed to be translated into proteins (L10a is part of the translational machinery). Six mice for each vigilant state group (sleep (S), waking (W), and sleep deprivation (SD)) were considered. For each animal, cerebral cortex was dissected and immediately processed. Samples were immunoprecipitated to isolate astrocytes. The precipitated portion formed the bound sample (IP) containing astrocytes and the remaining part formed the unbound sample (UB) containing all the remaining cell types (neurons and other glia cells). Then, both IP and UB samples were processed and RNA was extracted. All the IP samples (n=18) were then hybridized to Affymetrix GeneChip Mouse Genome 430 2.0 arrays, while UB samples were pooled together in two biological replicates (UB1+UB2+UB3 and UB4+UB5+UB6) for each group (n=6 in total) and then hybridized to Affymetrix GeneChip Mouse Genome 430 2.0 arrays.
2015-07-08 | E-GEOD-69079 | biostudies-arrayexpress
Project description:Familial amyotrophic lateral sclerosis (ALS) represents about 10% of ALS cases. In about 20% of familial ALS patients, a mutation in superoxide dismutase-1 (SOD1) can be found. The ubiquitous SOD1 protein converts superoxide radical anions to oxygen and hydrogen peroxide. Patients with familial ALS caused by mutations in SOD1 can show comorbidity with frontotemporal dementia and develop cognitive impairment, including apathy, inattention, verbal deficits, and hypersexuality. At the cellular level, pathological signs of ALS may include tau immunoreactive astrocytic and neuronal inclusions, suggesting that cognitive dysfunction in ALS may also reflect abnormal protein metabolism of the microtubule associated protein (MAP), tau. To identify cell-specific expression changes, we performed laser capture microdissection (LCM) to isolate anterior horn motor neurons and surrounding cells. To determine common pathways for the development of ALS due to dysfunction of SOD1 or TAU, we performed whole transcriptome analysis in SOD1 and TAU mouse models. Because ALS is a neurodegenerative disease that specifically affects motor neurons, these cells were the main investigative target. Global transcriptomes of glial cells surrounding the motor neurons were also assessed, because these cells have been implicated as triggers of neurodegeneration. Mouse experiments were performed at the presymptomatic stage, prior to the onset of cell loss, in order to reduce false positive signals due to tissue reactive changes. Lumbar anterior horn anterior horn motor neurons and surrounding cells (glia) were isolated from presymptomatic TAU-P301L and SOD1-G93A transgenic mice using laser capture microdissection (LCM; PixCell® IIe LCM System, Arcturus, Molecular Devices, CA). On average, 500 motor neuron bodies or surrounding glial cells from 20 tissue sections per animal were collected. RNA isolation from LCM collected cells was performed using the Qiagen RNeasy Micro Kit. Only RNA with RNA Integrity Numbers (RIN) above 7.5 were taken for further analysis (Agilent Bioanalyzer 2100). A two-round T7-based amplification and labeling protocol (Agilent Low RNA Input Linear Amplification Kit PLUS) was used to generate high quality labeled cRNA. Agilent Whole Mouse Genome Microarray comparisons of motor neurons and surrounding glia were performed between transgenic (SOD1G93A and TAUP301L) and corresponding nontransgenic (control) littermate animals, producing four independent comparison groups: SOD1G93A motor neurons versus control motor neurons (SOD1mn), SOD1G93A motor neuron surrounding glia versus control glia (SOD1gl), TAUP301L motor neurons versus control motor neurons (TAUmn) and TAUP301L glia versus control glia (TAUgl). Each comparison used four pairs of transgenic (SOD1G93A or TAUP301L) vs. corresponding control littermate animals, producing four biological replicates. Raw microarray data were acquired using the Agilent DNA Microarray scanner and processed with the accompanying Agilent Feature Extraction 10.5 Image Analysis software using default settings. Normalized signal intensities were used to identify gene expression changes in SOD1G93A and TAUP301L motor neurons and surrounding glial cells, generating four partially overlapping sets of data. For the identification of differential expression, the genes were required to pass two conservative criteria: a ratio beyond the 99.5% confidence interval observed in homotypic comparisons, which corresponded to an approximately 1.5-fold expression change, and a paired t-test (P<0.01) computed using 100 permutations of the data for each gene. Correction for multiple comparisons was performed using the adjusted Bonferroni test. The analysis was performed in the TM4: Microarray Software Suite. These techniques identified 251 transcripts representing 186 known genes for which expression was altered in at least one of the four comparisons. Four-condition experiment, SOD1G93A motor neurons versus control motor neurons (SODmn), SOD1G93A motor neuron surrounding glia versus control glia (SODgl), TAUP301L motor neurons versus control motor neurons (TAUmn) and TAUP301L glia versus control glia (TAUgl). Each comparison used four pairs of transgenic (SOD1G93A or TAUP301L) vs. corresponding control littermate animals, producing four biological replicates. Biological replicates: 4 SOD1G93A motor neurons (SODmn), 4 non SOD littermate motor neurons (nonSODmn), 4 SOD1G93A motor neuron surrounding glia (SODgl), 4 non SOD littermate motor neuron surrounding glia (nonSODgl), 4 TAUP301L motor neurons (TAUmn), 4 non TAU littermate motor neurons (nonTAUmn), 4 TAUP301L motor neuron surrounding glia (TAUgl), 4 non TAU littermate motor neuron surrounding glia (nonTAUgl). Four independent comparison groups were generated: SOD1G93A motor neurons versus control nonSOD motor neurons, SOD1G93A motor neuron surrounding glia versus control nonSOD glia, TAUP301L motor neurons versus control nonTAU motor neurons and TAUP301L glia versus control nonTAU glia. Each comparison used four pairs of transgenic (SOD1G93A or TAUP301L) vs. corresponding control littermate animals, producing four biological replicates. Each replicate was repeated twice with dye flip to correct for unequal dye incorporation rates. Therefore, eight microarray hybridizations were performed for each biological comparison, for a total of 32 microarray slides and generating four groups of differentially expressed genes in SOD1G93A motor neurons (SODmn), SOD1G93A motor neuron surrounding glial cells (SODgl), TAUP301L motor neurons (TAUmn), and TAUP301L surrounding glial cells (TAUgl).
2010-07-30 | E-GEOD-22482 | biostudies-arrayexpress
Project description:Ischemic stroke is a serious medical condition that leads to neurological symptoms such as loss of motor and cognitive function. Focal cerebral ischemia (FCI) occurs due to interruption of blood supply to the site of injury, leading to the death of brain cells. Cells carrying Neural-glial antigen 2 (NG2) include glial cells serving primarily as olidogendrocyte precursors and a portion of pericytes. NG2 glia proliferate rapidly after ischemia and migrate to the site of injury, participate with astrocytes in glial scar formation, and contribute to the regeneration of the brain tissue. The ability of NG2 glia to differentiate into a different cell type than oligodendrocytes has been described but is still controversial. We therefore isolated NG2 cells and their derivatives labeled with tdTomato red fluorescent protein from the cortex of Rosa26-tdTomato/Cspg4-CreERT2 mice three days after middle cerebral artery occlusion (MCAO). Sham-operated animals were used as healthy controls (CTRL). We aimed to identify NG2 cell types and their derivatives in the cortex of healthy and ischemic mice and determine their incidence as well as characteristic gene expression.
2023-09-21 | E-MTAB-11967 | biostudies-arrayexpress
Project description:<p>We sought to characterize cellular heterogeneity in the human cerebral cortex at a molecular level during cortical neurogenesis. We captured single cells and generated sequencing libraries using the C1TM Single-Cell Auto Prep System (Fluidigm), the SMARTer Ultra Low RNA Kit (Clontech), and the Nextera XT DNA Sample Preparation Kit (Illumina). We performed unbiased clustering of the single cells and further examined transcriptional variation among cell groups interpreted as radial glia. Within this population, the major sources of variation related to cell cycle progression and the stem cell niche from which radial glia were captured. We found that outer subventricular zone radial glia (oRG cells) preferentially express genes related to extracellular matrix formation, migration, and stemness, including <i>TNC</i>, <i>PTPRZ1</i>, <i>FAM107A</i>, <i>HOPX</i>, and <i>LIFR</i> and related this transcriptional state to the position, morphology, and cell behaviors previously used to classify the cell type. Our results suggest that oRG cells maintain the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby contributing to the developmental and evolutionary expansion of the human neocortex.</p> <p>For <b>study version 2</b>, we have updated this data set to include additional primary cells that we infer to represent microglia, endothelial cells, and immature astrocytes, as well as additional cells from the developing neural retina, and from iPS-cell derived cerebral organoids. The genes distinguishing these cell populations may reveal biological processes supporting the diverse functions of these cell types as well as vulnerabilities of specific cell types in human genetic diseases and in viral infections.</p> <p>For <b>study version 3</b>, we have updated the data set to include additional primary cells, including those published in Nowakowski, et al., Science 2017: "Spatiotemporal Gene Expression Trajectories Reveal Developmental Hierarchies of the Human Cortex" (<i>in press</i>)</p>
| phs000989 | dbGaP