Shared inflammatory glial cell signature after stab wound injury, revealed by spatial, temporal, and cell-type-specific profiling of the murine cerebral cortex DOI Creative Commons
Christina Koupourtidou, Veronika Schwarz, Hananeh Aliee

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 3, 2024

Traumatic brain injury leads to a highly orchestrated immune- and glial cell response partially responsible for long-lasting disability the development of secondary neurodegenerative diseases. A holistic understanding mechanisms controlling responses specific types their crosstalk is required develop an efficient strategy better regeneration. Here, we combine spatial single-cell transcriptomics chart transcriptomic signature injured male murine cerebral cortex, identify states different cells contributing this signature. Interestingly, distinct share large fraction injury-regulated genes, including inflammatory programs downstream innate immune-associated pathways Cxcr3 Tlr1/2. Systemic manipulation these decreases reactivity state associated with poor The functional relevance discovered shared highlights importance our resource enabling comprehensive analysis early events after injury.

Language: Английский

Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration DOI
Rickie Patani, Giles E. Hardingham, Shane A. Liddelow

et al.

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(7), P. 395 - 409

Published: June 12, 2023

Language: Английский

Citations

242
Solving neurodegeneration: common mechanisms and strategies for new treatments DOI Creative Commons
Lauren K. Wareham, Shane A. Liddelow, Sally Temple

et al.

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: March 21, 2022

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology site disease pathology. To address these and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus the Melza M. Frank Theodore Barr Foundation collaborated to bring together key opinion leaders experts field for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style focused uncovering mechanistic roots promising new catalyzed by goal finding treatments glaucoma, world's leading cause irreversible blindness interest three hosting foundations. Glaucoma, which causes vision loss through degeneration optic nerve, likely shares early cellular molecular events with other diseases central nervous system. Here we major areas overlap between system: neuroinflammation, bioenergetics metabolism, genetic contributions, neurovascular interactions. We summarize important discussion points emphasis research that are most innovative treatment neurodegeneration yet require further development. The is highlighted provides unique opportunities collaboration will lead efforts preventing ultimately loss.

Language: Английский

Citations

196
Astrocytes in human central nervous system diseases: a frontier for new therapies DOI Creative Commons
Alexei Verkhratsky, Arthur M. Butt, Baoman Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Oct. 13, 2023

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence the central nervous system (CNS). contribute pathophysiology all neurological neuropsychiatric disorders in ways that can be either beneficial or detrimental disorder outcome. Pathophysiological changes astroglia primary secondary result gain loss functions. respond external, non-cell autonomous signals associated with any form CNS pathology by undergoing complex variable their structure, molecular expression, function. In addition, internally driven, cell astroglial innate properties lead pathologies. Astroglial is complex, different pathophysiological states phenotypes context-specific vary disorder, disorder-stage, comorbidities, age, sex. Here, we classify into (i) reactive astrogliosis, (ii) atrophy function, (iii) degeneration death, (iv) astrocytopathies characterised aberrant forms drive disease. We review across spectrum human diseases disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack epilepsy, as well neurodevelopmental, neurodegenerative, metabolic disorders. Characterising cellular mechanisms represents new frontier identify novel therapeutic strategies.

Language: Английский

Citations

159
Single-cell and spatial transcriptomics: deciphering brain complexity in health and disease DOI Open Access
Monika Piwecka, Nikolaus Rajewsky, Agnieszka Rybak‐Wolf

et al.

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(6), P. 346 - 362

Published: May 17, 2023

Language: Английский

Citations

156
Microglia as hackers of the matrix: sculpting synapses and the extracellular space DOI Creative Commons
Joshua Crapser, Miguel A. Arreola, Kate I. Tsourmas

et al.

Cellular and Molecular Immunology, Journal Year: 2021, Volume and Issue: 18(11), P. 2472 - 2488

Published: Aug. 19, 2021

Abstract Microglia shape the synaptic environment in health and disease, but synapses do not exist a vacuum. Instead, pre- postsynaptic terminals are surrounded by extracellular matrix (ECM), which together with glia comprise four elements of contemporary tetrapartite synapse model. While research this area is still just beginning, accumulating evidence points toward novel role for microglia regulating ECM during normal brain homeostasis, such processes may, turn, become dysfunctional disease. As it relates to synapses, reported modify perisynaptic matrix, diffuse that surrounds dendritic axonal terminals, as well perineuronal nets (PNNs), specialized reticular formations compact enwrap neuronal subsets stabilize proximal synapses. The interconnected relationship between they embedded suggests alterations one structure necessarily affect dynamics other, may need sculpt within. Here, we provide an overview microglial regulation PNNs, propose candidate mechanisms these structures be modified, present implications modifications homeostasis

Language: Английский

Citations

107
CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states DOI
Kun Leng, Indigo V.L. Rose, Hyosung Kim

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(11), P. 1528 - 1542

Published: Oct. 27, 2022

Language: Английский

Citations

97
Smart Nanomedicine to Enable Crossing Blood–Brain Barrier Delivery of Checkpoint Blockade Antibody for Immunotherapy of Glioma DOI
Hairong Wang, Yu Chao, He Zhao

et al.

ACS Nano, Journal Year: 2022, Volume and Issue: 16(1), P. 664 - 674

Published: Jan. 3, 2022

Immune checkpoint blockade (ICB) therapy has shown tremendous promises in the treatment of various types tumors. However, ICB with antibodies appears to be less effective for glioma, partly owing existence blood–brain barrier (BBB) that impedes entrance therapeutics including most proteins central nervous system (CNS). Herein, considering widely existing nicotinic acetylcholine receptors (nAChRs) and choline transporters (ChTs) on surface BBB, a analogue 2-methacryloyloxyethyl phosphorylcholine (MPC) is employed fabricate BBB-crossing copolymer via free-radical polymerization, followed by conjugation antiprogrammed death-ligand 1 (anti-PD-L1) pH-sensitive traceless linker. The obtained nanoparticles exhibit significantly improved capability receptor-mediated transportation after intravenous injection an orthotopic glioma tumor model. Within acidic microenvironment, anti-PD-L1 would released from such pH-responsive nanoparticles, further triggering highly prolong animal survival. This work thus realizes microenvironment responsive delivery antibodies, promising next generation immunotherapy glioma.

Language: Английский

Citations

79
The Neurovasculome: Key Roles in Brain Health and Cognitive Impairment: A Scientific Statement From the American Heart Association/American Stroke Association DOI Open Access
Costantino Iadecola, Eric E. Smith, Josef Anrather

et al.

Stroke, Journal Year: 2023, Volume and Issue: 54(6)

Published: April 3, 2023

Preservation of brain health has emerged as a leading public priority for the aging world population. Advances in neurovascular biology have revealed an intricate relationship among cells, meninges, and hematic lymphatic vasculature (the neurovasculome) that is highly relevant to maintenance cognitive function. In this scientific statement, multidisciplinary team experts examines these advances, assesses their relevance disease, identifies knowledge gaps, provides future directions.

Language: Английский

Citations

79
Droplet-based forward genetic screening of astrocyte–microglia cross-talk DOI
Michael A. Wheeler, Iain C. Clark, Hong‐Gyun Lee

et al.

Science, Journal Year: 2023, Volume and Issue: 379(6636), P. 1023 - 1030

Published: March 10, 2023

Cell-cell interactions in the central nervous system play important roles neurologic diseases. However, little is known about specific molecular pathways involved, and methods for their systematic identification are limited. Here, we developed a forward genetic screening platform that combines CRISPR-Cas9 perturbations, cell coculture picoliter droplets, microfluidic-based fluorescence-activated droplet sorting to identify mechanisms of cell-cell communication. We used SPEAC-seq (systematic perturbation encapsulated associated cells followed by sequencing), combination with vivo microglia-produced amphiregulin as suppressor disease-promoting astrocyte responses multiple sclerosis preclinical models clinical samples. Thus, enables high-throughput communication mechanisms.

Language: Английский

Citations

74
Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets DOI Creative Commons
Bruna R. Kouba, Laura A. Borba, Pedro Borges de Souza

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(5), P. 423 - 423

Published: Feb. 28, 2024

The involvement of central and peripheral inflammation in the pathogenesis prognosis major depressive disorder (MDD) has been demonstrated. increase pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-18, TNF-α) individuals with depression may elicit neuroinflammatory processes inflammation, mechanisms that, turn, can contribute to gut microbiota dysbiosis. Together, neuroinflammation dysbiosis induce alterations tryptophan metabolism, culminating decreased serotonin synthesis, impairments neuroplasticity-related mechanisms, glutamate-mediated excitotoxicity. This review aims highlight inflammatory (neuroinflammation, dysbiosis) involved pathophysiology MDD explore novel anti-inflammatory therapeutic approaches for this psychiatric disturbance. Several lines evidence have indicated that addition antidepressants, physical exercise, probiotics, nutraceuticals (agmatine, ascorbic acid, vitamin D) possess effects their antidepressant properties. Further studies are necessary benefits these alternative therapies MDD.

Language: Английский

Citations

73