Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA139561 | ENA |
REPOSITORIES: ENA
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Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder that threatens to reach epidemic proportions as our population ages. Although much research has examined molecular pathways associated with AD, relatively few studies have focused on critical early stages. Our prior microarray study correlated gene expression in human hippocampus with AD markers. Results suggested a new model of early-stage AD in which pathology spreads along myelinated axons, orchestrated by upregulated transcription and epigenetic factors related to growth and tumor suppression (Blalock et al., 2004). However, the microarray analyses were performed on RNA from fresh frozen hippocampal tissue blocks containing both gray and white matter, potentially obscuring region-specific changes. In the present study, we used laser capture microdissection to exclude major white matter tracts and selectively collect CA1 hippocampal gray matter from formalin-fixed, paraffin-embedded (FFPE) hippoc ampal sections of the same subjects assessed in our prior study. Microarray analyses of this gray matter-enriched tissue revealed many correlations similar to those seen in our prior study, particularly for neuron-related genes. Nonetheless, in the laser-captured tissue, we found a striking paucity of the AD-associated epigenetic and transcription factor genes that had been strongly overrepresented in the prior tissue block study. In addition, we identified novel pathway alterations that may have considerable mechanistic implications, including downregulation of genes stabilizing ryanodine receptor Ca2+ release and upregulation of vascular development genes. We conclude that FFPE tissue can be a reliable resource for microarray studies, that upregulation of growth-related epigenetic/ transcription factors with incipient AD is predominantly localized to white matter, further supporting our prior findings and model, and that alterations in vascular and ryanodine receptor-relat ed pathways in gray matter are closely associated with incipient AD.
2011-08-01 | GSE28146 | GEO
Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder that threatens to reach epidemic proportions as our population ages. Although much research has examined molecular pathways associated with AD, relatively few studies have focused on critical early stages. Our prior microarray study correlated gene expression in human hippocampus with AD markers. Results suggested a new model of early-stage AD in which pathology spreads along myelinated axons, orchestrated by upregulated transcription and epigenetic factors related to growth and tumor suppression (Blalock et al., 2004). However, the microarray analyses were performed on RNA from fresh frozen hippocampal tissue blocks containing both gray and white matter, potentially obscuring region-specific changes. In the present study, we used laser capture microdissection to exclude major white matter tracts and selectively collect CA1 hippocampal gray matter from formalin-fixed, paraffin-embedded (FFPE) hippoc ampal sections of the same subjects assessed in our prior study. Microarray analyses of this gray matter-enriched tissue revealed many correlations similar to those seen in our prior study, particularly for neuron-related genes. Nonetheless, in the laser-captured tissue, we found a striking paucity of the AD-associated epigenetic and transcription factor genes that had been strongly overrepresented in the prior tissue block study. In addition, we identified novel pathway alterations that may have considerable mechanistic implications, including downregulation of genes stabilizing ryanodine receptor Ca2+ release and upregulation of vascular development genes. We conclude that FFPE tissue can be a reliable resource for microarray studies, that upregulation of growth-related epigenetic/ transcription factors with incipient AD is predominantly localized to white matter, further supporting our prior findings and model, and that alterations in vascular and ryanodine receptor-relat ed pathways in gray matter are closely associated with incipient AD. RNA was extracted using RecoverAll Total Nucleic Acid Isolation Kit for FFPE (Ambion) according to manufacturer’s instructions (3h incubation at 55 C followed by glass fiber filtration). This system has recently been shown to outperform other FFPE methods/ kits regarding yield of amplifiable RNA (Okello et al., 2010). Quality assessment of extracted material was performed with the Paradise Reagent Quality Assessment Kit (Molecular Devices), as well as via NanoDrop (Thermoscientific). All samples yielded sufficient genetic material (>50 ng) for subsequent reactions. 50 ng of extracted purified nucleic acid underwent RNA amplification using WT-Ovation FFPE System (NuGen) followed by FL-Ovation cDNA Biotin Module V2 (NuGen) for labeling and microarray (Affymetrix HGU133 v2) hybridization. All 30 microarrays (one per specimen) performed within acceptable limits (Scaling factor: 32.6 +/- 3.7; RawQ: 1.28 +/- 0.01; GapDH 3’:5’: 1.48 +/- 0.08; % present 35.4 +/- 1.5) and were not significantly different across treatment (p < 0.5 for all measures, 1-ANOVA). In general, these results indicate a smaller signal in laser captured FFPE samples than in prior fresh frozen samples (Scaling factor: 5.9 +/- 0.6; RawQ 2.7 +/- 0.04; GapDH 3’:5’: 3.65 +/- 0.55; % present: 44.6 +/- 1.1) with an increased scaling factor decreased RawQ and reduced % present all indicating reduced signal volume, while the smaller GapDH ratio suggests more degraded material- consistent with other reports of the dynamics of small FFPE sample results. Further, the % present call, while lower than found in fresh frozen tissue, is much greater than would be expected by chance (5%).This suggests that the extracted genetic material still contains a large amount of valid data. Probe sets were annotated, and transcriptional profiles were generated, using the MAS5 algorithm and annotation data sets (Affymetrix Expression Console v. 1.1; HGU133 annotation October, 2003) in order to facilitate comparison with prior work. Results were filtered for presence, redundancy, and annotation status and analyzed by Pearson’s test for correlation with each subject’s Mini-Mental Status Exam (MMSE) score and Neurofibrillary Tangle (NFT) counts. The false discovery rate (FDR) (Hochberg and Benjamini, 1990) was used to estimate the error of multiple testing’s contribution to False Positives and the DAVID suite of bioinformatic tools was used to identify transcriptional pathways using the ‘table cluster’ option.
2011-07-31 | E-GEOD-28146 | biostudies-arrayexpress
Project description:Objective: We previously reported that white matter connexin43 (Cx43) may related to the severity of the multiple sclerosis (MS), whereas the role of gray matter Cx43 in demyelinating disease is unknown. It was considered MS lesions were only exist in white matter, but recent studies revealed that demyelinating lesions are also exist in the cerebral cortex. This fact suggest the possibility that gray matter is somewhat related to the pathophysiology of MS. In this study, we aimed to clarify the role of gray matter Cx43 in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Methods: We developed Cx43F/F;Glutamate aspartate transporter (GLAST)-CreER(T2)KI/+ mice as gray matter specific Cx43 conditional knock-out (Cx43cKO) mice. We induced MOG-EAE 10 days after tamoxifen injection, and analyze its clinical course and pathology. We used Cx43F/F mice as controls. Results: EAE was significantly milder in gray matter astrocyte-specific Cx43cKO mice from acute phase to chronic phase, as compared with control mice. Pathology demonstrated less demyelinating lesions and infiltrating cells. Infiltrating immune cells did not express Cx43 in the active demyelinating lesions of the lumbar cord in both groups. The expression level of Cx43 was similar between these two groups in the spleen and the inguinal lymph nodes. Interpretation: Acute KO of gray matter specific Cx43 before induction of EAE reduce its aggressiveness. This finding may suggest the possibility that gray matter Cx43 modify the MS pathophysiology.
2021-04-20 | GSE148929 | GEO
Project description:Objective: We previously reported that white matter connexin43 (Cx43) may related to the severity of the multiple sclerosis (MS), whereas the role of gray matter Cx43 in demyelinating disease is unknown. It was considered MS lesions were only exist in white matter, but recent studies revealed that demyelinating lesions are also exist in the cerebral cortex. This fact suggest the possibility that gray matter is somewhat related to the pathophysiology of MS. In this study, we aimed to clarify the role of gray matter Cx43 in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Methods: We developed Cx43F/F;Glutamate aspartate transporter (GLAST)-CreER(T2)KI/+ mice as gray matter specific Cx43 conditional knock-out (Cx43cKO) mice. We induced MOG-EAE 10 days after tamoxifen injection, and analyze its clinical course and pathology. We used Cx43F/F mice as controls. Results: EAE was significantly milder in gray matter astrocyte-specific Cx43cKO mice from acute phase to chronic phase, as compared with control mice. Pathology demonstrated less demyelinating lesions and infiltrating cells. Infiltrating immune cells did not express Cx43 in the active demyelinating lesions of the lumbar cord in both groups. The expression level of Cx43 was similar between these two groups in the spleen and the inguinal lymph nodes. Interpretation: Acute KO of gray matter specific Cx43 before induction of EAE reduce its aggressiveness. This finding may suggest the possibility that gray matter Cx43 modify the MS pathophysiology.
2021-04-20 | GSE148931 | GEO
Project description:Microglia/macrophages line the border of demyelinated lesions in both cerebral white matter and cortex in multiple sclerosis brains. Microglia/macrophages associated with chronic white-matter lesions are thought to be responsible for slow lesion expansion and disability progression in progressive multiple sclerosis whereas those lining gray matter lesions are less studied. Profiling these microglia/macrophages could help to focus therapies on genes or pathways specific to lesion expansion and disease progression. We compared the morphology and transcript profiles of microglia/macrophages associated with borders of white matter (WM line) and subpial gray matter lesions (GM line) using laser capture microscopy. We performed RNAseq on isolated cells followed by immunocytochemistry to determine distribution of translational products of transcripts increased in WM line. Cells in WM line appear activated with shorter processes and larger cell bodies, whereas those in GM Line appear more homeostatic with smaller cell bodies and multiple thin processes. Transcript profiling revealed 176 genes in WM lines and 111 genes in GM lines as differentially expressed. Transcripts associated with immune activation and iron homeostasis were increased in WM line whereas genes belonging to canonical Wnt signaling pathway were increased in GM line. We propose that mechanisms of demyelination and dynamics of lesion expansion are responsible for differential transcript expression in WM lines and GM lines, and posit that increased expression of Fc epsilon receptor, spleen tyrosine kinase, and Bruton’s tyrosine kinase play a key role in regulating microglia/macrophage function at the border of chronic active white matter lesions.
2024-05-05 | GSE255290 | GEO
Project description:Astrocytes play essential roles in the developing nervous system, including supporting synapse function. These astrocyte support functions emerge coincident with brain maturation and may be tailored in a region-specific manner. For example, gray matter astrocytes have elaborate synapse-associated processes and are morphologically and molecularly distinct from white-matter astrocytes. This raises the question of whether there are unique environmental cues that promote gray matter astrocyte identity and synaptogenic function. We previously identified adrenergic receptors as preferentially enriched in developing gray versus white matter astrocytes, suggesting that noradrenergic signaling could be a cue that promotes the functional maturation of gray matter astrocytes. We first characterized noradrenergic projections during postnatal brain development in mouse and human, finding that process density was higher in the gray matter and increased concurrently with astrocyte maturation. RNA-sequencing revealed that astrocytes in both species expressed ɑ and β adrenergic receptors. We found that stimulation of β adrenergic receptors increased primary branching of rodent astrocytes in vitro. Conversely, astrocyte-conditional knockout of the β1 adrenergic receptor reduced the size of gray matter astrocytes, and led to dysregulated sensorimotor integration in female mice. These studies suggest that adrenergic signaling to developing astrocytes impacts their morphology and has implications for adult behavior, particularly in female animals. More broadly, they demonstrate a mechanism through which environmental cues impact astrocyte development. Given the key roles of norepinephrine in brain states such as arousal, stress, and learning, these findings could prompt further inquiry into how developmental stressors impact astrocyte development and adult brain function.
2023-12-27 | GSE235840 | GEO
Project description:Around 25% of stroke survivors over 65 years old develop progressive cognitive decline more than 3 months post-stroke, with features of vascular dementia. Poststroke dementia (PSD) is associated with pathology in frontal brain regions, in particular dorsal lateral prefrontal cortex (DLPFC) neurons and white matter, remote from the infarct, implicating damage to anterior cognitive circuits (ACC) involved in impaired executive function. We hypothesised that PSD results from progressive neuronal damage in the DLPFC and that this is associated with alterations in the gliovascular unit (GVU) of frontal white matter. We aimed to identify the cellular and molecular basis of PSD by investigating the transcriptomic profile of the neurons and white matter GVU cells previously implicated in pathology. Laser capture microdissected neurons, astrocytes and endothelial cells were obtained from the Cognitive Function After Stroke (COGFAST) cohort. Gene expression was assessed using microarrays and pathways analysis to compare changes in PSD with controls and with poststroke non-dementia (PSND). Laser captured microdissected neurons were obtained from the bilateral carotid artery stenosis (BCAS) model and equivalent SHAM animals
2022-06-01 | GSE186798 | GEO
Project description:Neurodegenerative diseases characterized by tau aggregates have distinct tau pathological profiles that may differ in relation to the morphology and structure of the filaments, the tau-isoform composition and the cell types and brain areas that are affected. Neurons, dendrites and axonal terminals are situated in the gray matter, whereas axonal tracts and oligodendrocytes are prominent in the white matter. Whilst astrocytes and other glial cells are found throughout both gray and white matter, oligodendrocytes are preferentially located in the white matter, where their role is to myelinate axonal nerve fibers. Recently, the atomic structures of tau filaments isolated from samples from gray matter, which contains predominantly neuronal tau, have been characterized. Whether glial tau fibrils share a common fold with neuronal tau fibrils in the same disease remains unknown. Using cryogenic electron microscopy (cryo-EM), we determined for the first time the structure of tau filaments from gray and white matter. We isolated tau post-mortem from the brain of two individuals with multiple system tauopathy with presenile dementia (MSTD) caused by the +3 mutation in MAPT and determined that they have identical structures (the AGD type 2 fold). In addition, we identified and determined the structure of TMEM106B in gray and white matter regions of the brain of the same individuals. Our findings support the notion that in the same disease there is not a region/cell type-specific form of tau or TMEM106B, and that a similar mechanism of fibrillization and/or transmission in neuronal and glial cell types may exist. Whether TMEM106B fibrils represent a true age or disease related process remains to be fully determined.
2022-12-06 | MSV000090845 | MassIVE
Project description:We investigated spatiotemporal molecular patterns related to AD pathophsiology using spatially resolved transcriptome of the AD mouse model. The late change of gray matters of AD was commonly related to neuroinflammation, while the early change in the white matter of AD represented neuronal projection and ensheathment of axons before the amyloid plaques accumulation. Disease-associated microglia and astrocyte signatures were spatially differently enriched. Our results provide a key spatiotemporally heterogeneous molecular change particularly related to inflammation in AD.
2024-01-10 | GSE174321 | GEO
Project description:Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by increased inflammation and immune responses, oxidative injury, mitochondrial dysfunction, and iron dyshomeostasis leading to demyelination and axonal damage. In MS, incomplete remyelination results in chronically demyelinated axons and degeneration coinciding with disability. This suggests a failure in the ability to remyelinate in MS, however, the precise underlying mechanisms remain unclear. We aimed to identify proteins whose expression was altered in chronic inactive white matter lesions and periplaque white matter in MS tissue to reveal potential pathogenic mechanisms. Laser capture microdissection coupled to proteomics was used to interrogate spatially preserved changes in formalin-fixed paraffin-embedded brain tissue from chronic MS individuals and controls with no apparent neurological complications. Histopathological maps guided the capture of inactive lesions, periplaque white matter, and cortex from chronic MS individuals along with corresponding white matter and cortex from control tissue. Label free quantitation by liquid chromatography tandem mass spectrometry was used to discover differentially expressed proteins between the various brain regions. In addition to confirming loss of several myelin-associated proteins known to be affected in MS, proteomics analysis of chronic inactive MS lesions revealed alterations in myelin assembly, metabolism, and cytoskeletal organization. Notably, a subset of proteins that were altered in MS white matter indicate altered lipid metabolism. Our findings highlight proteome changes in chronic inactive MS white matter lesions and periplaque white matter, which may be crucial for proper myelinogenesis, bioenergetics, focal adhesions, and cellular function. These findings highlight the importance and feasibility of spatial approaches such as laser capture microdissection-based proteomics analysis of pathologically distinct regions of MS brain tissue. Identification of spatially resolved changes in the proteome of MS brain tissue should aid in the understanding of pathophysiological mechanisms and the development of novel therapies.
2024-08-29 | PXD047800 | Pride