Transcriptomic diversity of cell types across the adult human brain

Science, Journal Year: 2023, Volume and Issue: 382(6667)

Published: Oct. 12, 2023

The human brain directs complex behaviors, ranging from fine motor skills to abstract intelligence, but the diversity of cell types that support these has not been fully described. In this work, we used single-nucleus RNA sequencing systematically survey cells across entire adult brain. We sampled more than three million nuclei approximately 100 dissections forebrain, midbrain, and hindbrain in postmortem donors. Our analysis identified 461 clusters 3313 subclusters organized largely according developmental origins revealing high midbrain neurons. Astrocytes oligodendrocyte-lineage also exhibited regional at multiple scales. transcriptomic census presented work provides a resource for understanding molecular health disease.

Language: Английский

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Microglia regulation of central nervous system myelin health and regeneration

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 24(1), P. 49 - 63

Published: July 14, 2023

Language: Английский

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Navigating oligodendrocyte precursor cell aging in brain health

Mechanisms of Ageing and Development, Journal Year: 2024, Volume and Issue: 220, P. 111959 - 111959

Published: June 29, 2024

Oligodendrocyte precursor cells (OPCs) comprise 5-8 % of the adult glial cell population and stand out as most proliferative type in central nervous system (CNS). OPCs are responsible for generating oligodendrocytes (OLs), myelinating CNS. However, OPC functions decline we age, resulting impaired differentiation inadequate remyelination. This review explores cellular molecular changes associated with aging, their impact on functionality. Furthermore, it examines aging within context multiple sclerosis Alzheimer's disease, both neurodegenerative conditions wherein aged exacerbate disease progression by impeding Moreover, various pharmacological interventions targeting pathways related to senescence discussed potential strategies rejuvenate OPCs. Enhancing our understanding mechanisms holds promise developing new therapies improve remyelination repair age-related disorders.

Language: Английский

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Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: April 9, 2022

Abstract The lack of understanding the cellular and molecular basis clinical genetic heterogeneity in progressive multiple sclerosis (MS) has hindered search for new effective therapies. Here, to address this gap, we analysed 632,000 single nuclei RNAseq profiles 156 brain tissue samples, comprising white matter (WM) lesions, normal appearing WM, grey (GM) lesions GM from 54 MS patients 26 controls. We observed expected changes overall neuronal glial numbers previously described within classical lesion subtypes. found highly cell type-specific gene expression tissue, with distinct differences between WM areas, confirming different pathologies. However, surprisingly, did not observe signatures types, rather a continuum change. This indicates that characterization better reflects abundance than type expression, global disease effect. Furthermore, major biological determinants variability samples relate individual patient effects, types or other metadata. identify four subgroups patterns oligodendrocyte stress and/or maturation, suggestive engagement pathological processes, an additional more variable regenerative astrocyte signature. discovery these patterns, which were also independent cohort, provides framework use biomarkers stratify optimal therapeutic approaches MS, significantly advances our mechanistic highlights need precision-medicine among patients.

Language: Английский

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Reduction of oxytocin-containing neurons and enhanced glymphatic activity in the hypothalamic paraventricular nucleus of patients with type 2 diabetes mellitus

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: July 3, 2023

Abstract Evidence from animal experiments has shown that the hypothalamic paraventricular nucleus (PVN) plays a key role in regulating body weight and blood glucose levels. However, it is unclear whether neuron populations human PVN are involved development of type 2 diabetes mellitus (T2DM). To address this, we investigated neuronal glial 26 T2DM patients 20 matched controls. Our findings revealed significant reduction oxytocin (Oxt) density compared to controls, while other remained unchanged. This suggests Oxt neurons may play specific pathophysiology T2DM. Interestingly, was accompanied by decreased melanocortinergic input as reflected alpha-MSH immunoreactivity. We also analysed two cell populations, they important for maintaining healthy neural microenvironment. found microglial density, phagocytic capacity, their proximity were not altered patients, indicating loss independent changes immunity. did observe number astrocytes, which crucial providing trophic support local neurons. Moreover, subpopulation astrocytes characterized aquaporin 4 expression overrepresented patients. Since this subset linked glymphatic system, overrepresentation might point alterations waste clearance system study shows selective individuals association with astrocytic gliovascular remodelling. Therefore, represent potential target treatment modalities.

Language: Английский

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Myelin basic protein mRNA levels affect myelin sheath dimensions, architecture, plasticity, and density of resident glial cells

Glia, Journal Year: 2024, Volume and Issue: 72(10), P. 1893 - 1914

Published: July 18, 2024

Myelin Basic Protein (MBP) is essential for both elaboration and maintenance of CNS myelin, its reduced accumulation results in hypomyelination. How different Mbp mRNA levels affect myelin dimensions across the lifespan how resident glial cells may respond to such changes are unknown. Here, investigate these questions, we used enhancer-edited mouse lines that accumulate ranging from 8% 160% wild type. In young mice, resulted corresponding decreases protein sheath thickness, confirming previously demonstrated rate-limiting role transcription control initial synthesis. However, despite maintaining lower line specific into old age, MBP thickness improved or fully normalized at rates defined by relative level. Sheath length, contrast, was affected only when were very low, demonstrating length not equally coupled Striking abnormalities structure also emerged with levels. Unexpectedly, an increase density all cell types arose response This investigation extends understanding plays elaboration, architecture, plasticity illuminates a novel axis crosstalk.

Language: Английский

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Monocarboxylate transporter 2 is required for the maintenance of myelin and axonal integrity by oligodendrocytes

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

ABSTRACT Neurodegenerative pathologies including multiple sclerosis (MS) are consistently associated with energy deficit in the central nervous system (CNS). This might directly impact myelinating oligodendrocytes as these particularly vulnerable to metabolic insults. Importantly, oligodendroglial dysfunction and myelin alterations occur most, if not all neurodegenerative diseases, axonal pathology/loss. Thus, elucidating mechanisms required for maintenance support be crucial identify therapeutic targets achieve neuroprotection. While monocarboxylates important fuels CNS, their role oligodendrocyte function remains unclear. Here we show that, just like neurons, express high affinity monocarboxylate transporter 2 (MCT2) both mice humans, which is downregulated progressive MS. deletion of MCT2 mouse did affect survival cells, it resulted downregulation lipid synthesis-associated enzymes failure maintenance. Moreover, upregulation lactate dehydrogenase A concomitant damage was observed but could alleviated by ketogenic diet. We conclude that support, becomes altered MS, may compensated specific therapies. Graphical abstract

Language: Английский

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Astrocyte heterogeneity reveals region-specific astrogenesis in the white matter

Nature Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Abstract Astrocyte heterogeneity has been well explored, but our understanding of white matter (WM) astrocytes and their distinctions from gray (GM) remains limited. Here, we compared cortical GM WM/corpus callosum (WM/CC) using single-cell RNA sequencing spatial transcriptomics the murine forebrain. The comparison revealed similarities also significant differences between WM astrocytes, including cytoskeletal metabolic hallmarks specific to with molecular properties shared human astrocytes. When two different regions, cortex cerebellum, found that they exhibited distinct, region-specific properties, cerebellum lacking, for example, a cluster expressing progenitor proliferation genes. Functional experiments confirmed astrocyte in WM/CC, not cerebellar WM, suggesting WM/CC may be source continued astrogenesis.

Language: Английский

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Design and Development of a Novel BET Protein-Targeted PET Imaging Probe for In Vivo Characterization of Alzheimer’s Disease Pathophysiology

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

BET proteins are essential epigenetic regulators involved in gene transcription and have been linked to neurodegenerative disorders, such as Alzheimer's disease (AD). In vivo imaging of may provide insights into pathophysiology help identify potential therapeutic targets. We developed a carbon-11-labeled radiotracer, [11C]YL9, which exhibits high binding affinity for proteins. It was synthesized via standard methylation evaluated brain uptake, specificity, pharmacokinetics wild-type AD mouse models using PET autoradiography. [11C]YL9 demonstrated excellent blood-brain barrier penetration, prolonged retention, strong protein binding. mice, uptake significantly higher than suggesting increased availability. These findings suggest that is promising radioligand noninvasive imaging. Its specificity favorable make it valuable tool studying involvement neurodegeneration.

Language: Английский

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Genetic association between gene expression profiles in oligodendrocyte precursor cells and psychiatric disorders

Frontiers in Psychiatry, Journal Year: 2025, Volume and Issue: 16

Published: April 22, 2025

Background Although neuronal dysfunction has been the focus of many studies on psychiatric disorders, accumulating evidence suggests that white matter abnormalities and oligodendrocyte lineage cells, including precursor cells (OPCs), play an important role. Beyond their established contribution to myelination, synaptic genes in OPCs form connections neurons influence circuits plasticity, thereby potentially contributing pathology. Methods We analyzed publicly available single–nucleus RNA sequencing (snRNA–seq) data from healthy donors with SCZ genome–wide association study (GWAS) summary statistics. assessed cell–type–specific enrichment SCZ–associated genetic variants performed weighted gene co–expression network analysis (WGCNA) identify disease–related modules implicated cell types. Results exhibited significant risk showed pronounced specificity expression patterns. Through WGCNA, we identified a distinct module was enriched for associated SCZ. Conclusion The present results highlight previously underappreciated role suggesting OPC–involved interactions may contribute pathophysiology This work underscores importance considering as active players neural dysfunction, potential implications future therapeutic strategies.

Language: Английский

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