White matter aging drives microglial diversity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA700408 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13648111.fastq.gz | Fastqsanger.gz | |||
| SRR13648112.fastq.gz | Fastqsanger.gz | |||
| SRR13648113.fastq.gz | Fastqsanger.gz | |||
| SRR13648114.fastq.gz | Fastqsanger.gz | |||
| SRR13648115.fastq.gz | Fastqsanger.gz |
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Project description:White matter aging drives microglial diversity
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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.
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Project description:White matter aging drives microglial diversity
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Project description:A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. Here, we found age-related alterations of oligodendrocytes with a reduction of total oligodendrocyte density in the aging murine white matter. Using single-cell RNA sequencing, we identify interferon-responsive oligodendrocytes, which localize in proximity of CD8+ T cells in the aging white matter. Absence of functional lymphocytes decreased oligodendrocyte reactivity and rescued oligodendrocyte loss, while T-cell checkpoint inhibition worsened the aging effect. In addition, we identified a subpopulation of immune cell dependent interferon-responsive microglia in the aging white matter, and co-culture experiments revealed that interferon- activated microglia triggered oligodendrocytes cell death. In summary, we provide evidence that T cells induced interferon-responsive oligodendrocytes and microglia are important modifiers of white matter aging.
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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.
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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.
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Project description:White matter hyperintensity (WMH) is a pressing global medical issue linked to cognitive decline and stroke risk. Despite its significance, the underlying mechanisms remain unclear. Here, we directly demonstrated in humans that high WMH burden correlated with delayed glymphatic pathway drainage. Additionally, a longitudinal cohort study revealed that glymphatic dysfunction predicted WMH progression. Next, in a rat model of WMH, we confirmed the presence of impaired lymphangiogenesis and glymphatic drainage, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis and glymphatic drainage through adenoviral delivery of Vascular Endothelial Growth Factor-C (VEGF-C) mitigated microglial gliosis and white matter demyelination. Conversely, blocking the growth of meningeal lymphatics with a VEGF-C trap strategy exacerbated these changes. Our findings highlight the role of meningeal lymphatics and glymphatic pathway dysfunction in aggravating brain white matter injury and advancing WMH, providing a potential novel strategy for WMH prevention and treatment.
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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.
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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.
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