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Transcriptomic analysis of age-associated periventricular lesions reveals dysregulation of the immune response

ABSTRACT: Age-associated Periventricular white matter lesions (PVL), reflecting white matter injury, are a common feature of the ageing brain. The aim of this study was to evaluate the transcriptomic profile of PVL using microarray analysis, in order to identify which pathways and/or gene expression changes may contribute to the pathogenesis of these lesions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157363 | GEO | 2020/11/18

REPOSITORIES: GEO

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A Dysregulated Proinflammatory Status in Preterm School-aged Children with PVL-induced Spastic Cerebral Palsy

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Project description:Injury occurring during critical periods of development may have long-term effects on inflammatory responses. Periventricular leukomalacia (PVL) is the most common cause of cerebral palsy (CP) in preterm infant. Activated leukocytes are the main source of inflammatory cytokines that give rise to white matter damage and CP in preterm infant. Here, we tested the hypothesis that inflammation profiles as pathogenic mediators for the occurrence of PVL in the neonatal period may persist in preterm children with CP at school age. Five preterm children with PVL-induced CP and gestational age-matched five preterm children with normal neurodevelopment were recruited from follow up clinics. Proinflammatory gene expression in the PBMCs from preterm children were determined by Superarray PCR study.

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The microglial transcriptome of age-associated deep subcortical white matter lesions suggests a neuroprotective response to blood-brain barrier dysfunction

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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Transcriptomic analysis of age-associated periventricular lesions reveals dysregulation of the immune response

Project description:Transcriptomic analysis of age-associated periventricular lesions reveals dysregulation of the immune response

| PRJNA661058 | ENA

From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions [RNA-seq]

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Gene expression changes in the periventricular white matter of neonatal piglets at a defined 48h time point following a hypoxic-ischemic insult: a comparison of piglets left untreated and those treated with a remote post-conditioning stimulus applied to the hind leg immediately after the insult.

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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.

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