Similar Datasets
Project description:White matter aging drives microglial diversity
| PRJNA700408 | ENA
Project description:White matter aging drives microglial diversity
| PRJNA701252 | ENA
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:The role of microglia in triggering the blood-brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion are unclear. Here we show that the vessel-adjacent microglia, that being specifically activated by plasma low-density lipoprotein (LDL) leakage during white matter damage, could induce demyelination and attenuate BBB integrity. We further show that LDL stimulation enhance microglial phagocytosis, resulting in over-engulfment of myelin debris, and overwhelming lipid metabolism balance in microglia. Unexpectedly, LDL-stimulated lipid-laden microglia exhibit a total suppressed profile of inflammatory responses, and compromised pro-regenerative properties. Overall, our study demonstrates that LDL-stimulated perivascular microglia show a particular disease-related molecular signature, characterized by suppressed regenerative properties, that is associated with the propagation of demyelination during white matter ischemia.
2025-04-12 | GSE229456 | GEO
Project description:Focal white matter lesions occur in most neurodegenerative disorders. Despite occurring early in disease, white matter lesions are considered either independent of, or secondary to, grey matter neuroinflammation, synapse loss and altered neuronal activity. Notably their functional impact on neuronal circuits has been understudied. To address this, we generated a focal white matter lesion in an anatomically well-defined circuit, in which white matter lesions occur in many neurodegenerative disorders. Here we show that focal white matter lesions evoke transient neuronal activity changes and microgliosis, with subsequent synapse loss and increased microglia engulfment in the grey matter, which is reversed if myelin regeneration completes. Grey matter microgliosis is often considered detrimental but we show that it is an integral part of the myelin regenerative process. When we prevent these transient changes in the grey matter, myelin regeneration is blocked in the white matter. Conversely, inducing myelin regeneration failure leads to chronic neuroinflammation in the grey matter, suggesting that myelin regeneration failure drives sustained grey matter microglial activation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration. Our findings reveal a form of regenerative plasticity coupling white matter integrity to grey matter function - a novel mechanism of neuroplasticity that may underlie multiple neurodegenerative conditions - and highlights the potential of targeting myelin regeneration to prevent chronic inflammation.
2026-02-05 | GSE311781 | GEO
Project description:LDL-stimulated microglial activation exacerbates white matter damage
| PRJNA954689 | ENA
Project description:Focal white matter lesions occur in most neurodegenerative disorders1-4. They are well characterised in multiple sclerosis (MS) but much less understood in other conditions. Despite occurring early in disease, white matter lesions are considered either independent of or secondary to grey matter neuroinflammation, synaptic loss and altered neuronal activity5-8. Notably their functional impact on neuronal circuits has been overlooked. To address this, we performed a focal white matter lesion in an anatomically well-defined circuit, in which white matter lesions occur in many neurodegenerative disorders. Here we show that focal white matter lesions evoke transient neuronal activity changes and microgliosis, synaptic loss and increased engulfment in the grey matter, which resolves by the time myelin regeneration completes. Synaptic loss and microgliosis are often considered detrimental but we show they are instead an integral part of the myelin regenerative process. When we prevent these transient changes in the grey matter, myelin regeneration is blocked in the white matter. Conversely, inducing myelin regeneration failure leads to chronic neuroinflammation in the grey matter, suggesting that myelin regeneration failure drives sustained microglial activation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration8-11. Hence, we present a novel mechanism that may underlie multiple conditions and highlight the potential of targeting myelin regeneration to prevent chronic neuroinflammation.
2026-02-10 | GSE274050 | 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: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.
2022-09-13 | GSE202579 | GEO