Similar Datasets
Project description:Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer’s disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood-brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mic. Sodium nitrate fortified drinking water provided to young and middle aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to spontaneous white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD.
2022-07-12 | GSE207693 | GEO
Project description:Vanishing white matter (VWM) is a leukodystrophy that primarily manifests in young children. In this disease, the brain white matter is differentially affected in a predictable pattern with telencephalic brain areas being more severely affected, while others remain allegedly completely spared. Using high-resolution mass spectrometry-based proteomics, we investigated the proteome patterns of the severely affected white matter in the frontal lobe and normal appearing pons in VWM and control cases to identify molecular bases underlying regional vulnerability. By comparing VWM patients to controls, we identified disease-specific proteome patterns. We showed substantial pathogenic changes in both the frontal white matter and pons at the protein level. Side-by-side comparison of brain region-specific proteome patterns further revealed regional differences. We found that different cell types are affected in the VWM frontal white matter than in the pons. Gene ontology and pathway analyses identified involvement of region distinct biological processes, of which pathways implicated in cellular respiratory metabolism were overarching features. In the VWM frontal white matter, proteome changes were associated with decrease in glycolysis/gluconeogenesis and metabolism of various amino acids. By contrast, in the VWM pons white matter, we found a decrease in oxidative phosphorylation. Taken together, our data show that brain regions are affected in parallel in VWM, but to different degrees. We found region-specific involvement of different cell types and discovered that cellular respiratory metabolism is differently affected across white matter regions in VWM. These region-specific changes help explain regional vulnerability to pathology in VWM.
2023-06-28 | PXD040861 | Pride
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:Age-associated deep-subcortical white matter lesions (DSCL) are an independent risk factor for dementia, displaying high levels of CD68+ microglia. This study aimed to characterise the transcriptomic profile of microglia in DSCL and surrounding radiologically normal-appearing white matter (NAWM) compared to non-lesional control white matter. CD68+ microglia were isolated from white matter groups (n=4 cases per group) from the Cognitive Function and Ageing Study neuropathology cohort by immuno-laser capture microdissection. Microarray gene expression profiling, but not RNA-sequencing, was found to be compatible with immuno-LCM-ed post-mortem material and identified significantly differentially expressed genes (DEG). Functional grouping and pathway analysis was assessed using DAVID, and immunohistochemistry was performed to validate gene expression changes at the protein level. Transcriptomic profiling of microglia in DSCL compared to non-lesional control white matter identified 181 significant DEG (93 upregulated and 88 downregulated). Functional clustering analysis revealed dysregulation of haptoglobin-hemoglobin binding (Enrichment score 2.15, p=0.017), confirmed by CD163 immunostaining, suggesting a neuroprotective microglial response to blood-brain barrier dysfunction in DSCL. In NAWM versus control white matter, microglia exhibited 347 DEGs (209 upregulated, 138 downregulated), with significant dysregulation of protein de-ubiquitination (Enrichment score 5.14, p<0.0001), implying an inability to maintain protein homeostasis in NAWM that may contribute to lesion spread. These findings enhance understanding of microglial transcriptomic changes in aging white matter pathology, highlighting a neuroprotective adaptation in DSCL microglia and a potentially lesion-promoting phenotype in NAWM microglia.
2024-05-01 | GSE260619 | GEO
Project description:Age-associated deep-subcortical white matter lesions (DSCL) are an independent risk factor for dementia, displaying high levels of CD68+ microglia. This study aimed to characterise the transcriptomic profile of microglia in DSCL and surrounding radiologically normal-appearing white matter (NAWM) compared to non-lesional control white matter. CD68+ microglia were isolated from white matter groups (n=4 cases per group) from the Cognitive Function and Ageing Study neuropathology cohort by immuno-laser capture microdissection. Microarray gene expression profiling, but not RNA-sequencing, was found to be compatible with immuno-LCM-ed post-mortem material and identified significantly differentially expressed genes (DEG). Functional grouping and pathway analysis was assessed using DAVID, and immunohistochemistry was performed to validate gene expression changes at the protein level. Transcriptomic profiling of microglia in DSCL compared to non-lesional control white matter identified 181 significant DEG (93 upregulated and 88 downregulated). Functional clustering analysis revealed dysregulation of haptoglobin-hemoglobin binding (Enrichment score 2.15, p=0.017), confirmed by CD163 immunostaining, suggesting a neuroprotective microglial response to blood-brain barrier dysfunction in DSCL. In NAWM versus control white matter, microglia exhibited 347 DEGs (209 upregulated, 138 downregulated), with significant dysregulation of protein de-ubiquitination (Enrichment score 5.14, p<0.0001), implying an inability to maintain protein homeostasis in NAWM that may contribute to lesion spread. These findings enhance understanding of microglial transcriptomic changes in aging white matter pathology, highlighting a neuroprotective adaptation in DSCL microglia and a potentially lesion-promoting phenotype in NAWM microglia.
2024-05-01 | GSE260815 | GEO
Project description:Aging results in both grey and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and grey matter separately, we identified white matter associated microglia (WAM), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by the activation of genes implicated in phagocytic activity and lipid metabolism. WAM depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAM form independently of apolipoprotein E (APOE), which is in contrast to mouse models of Alzheimer’s disease, in which microglia with WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAM. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAM may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease.
2021-02-18 | GSE166548 | GEO
Project description:Tissue progenitors maintain the integrity of organ systems through aging and stress. The brain’s white matter regions experience ischemic lesions and age-dependent degeneration. Brain white matter contains progenitors, oligodendrocyte precursor cells (OPCs), which can repair some insults. The response of OPCs to white matter ischemia and aging is not known. We characterized the response of OPCs to white matter stroke using OPC reporter mice, cell migration tracking, OPC specific RNA sequencing, and mechanistic studies in candidate biochemical pathways in the aged brain. White matter stroke induces initial proliferation of local OPCs but blocks differentiation, shunting a portion into astrocytes. Candidate signaling pathways for this differentiation block including novel interactions of inhibin and matrilin-2 and new roles of NgR1 ligands following white matter stroke. Stroke induces inhibin expression in astrocytes and downregulates OPC matrilin-2 that contributes into OPC differentiation block. Antagonism of NgR1 ligands promotes OPC differentiation by attenuating the OPC astrocytic transformation and enhances functional recovery from stroke in aged animals.
2019-11-15 | GSE53737 | GEO
Project description:White matter aging drives microglial diversity
2021-02-08 | GSE166304 | GEO
Project description:Gene expression profiling was performed on frontal and temporal cortex from vascular dementia (VaD), Alzheimer's disease (AD), and non-demented controls (Control) obtained from the University of Michigan Brain Bank. Controls and AD cases had no infarcts in the autopsied hemisphere. Vascular dementia cases had low Braak staging.
2019-04-23 | GSE122063 | GEO
Project description:Chronic alcohol consumption can lead to alchohol-related brain damage (ARBD). Despite the well known acute effects of alcohol the mechanism responsible for chronic brain damage is largely unknown. Pathologically the major change is the loss of white matter while neuronal loss is mild and restricted to a few areas such as the prefrontal cortex. In order to improve our understanding of ARBD pathogenesis we used microarrays to explore the white matter transcriptome of alcoholics and controls. Our results suggest that hepatic encephalopathy, along with two confounders, gray matter contamination and low RNA quality, are major drivers of gene expression in ARBD. All three exceeded the effects of alcohol itself. In particular, low quality RNA samples were characterized by an upregulation of protein translation machinery while hepatic encephalopathy was associated with a downregulation of mitochondrial energy metabolism pathways. The findings in HE alcoholics are consistent with the metabolic acidosis seen in this condition. In contrast non-HE alcoholics had widespread but only subtle changes in gene expression in their white matter. The initial cohort was compromised of four alcoholics without hepatic encephalopathy (non-HE alcoholics), three alcoholics with HE (HE alcoholics) and three neurologically normal controls. For each indvidual frozen white matter was sampled in the superior frontal gyrus (prefrontal cortex) and the precentral gyrus (motor cortex). These two cortices experience either moderate (prefrontal cortex) or no neuronal loss (motor cortex) with alcohol-related brain damage. Each white matter sample was divided in two before RNA was extracted to give two 'biological' repeats and a total of 40 samples. Subsequently eight duplicates were removed due to their gray matter contamination or low RNA quality to leave a 32-sample cohort (23 alcoholic (including eight with HE ) and nine control samples.
2014-01-04 | E-GEOD-53808 | biostudies-arrayexpress