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  1. Article ; Online: Fibrin promotes oxidative stress and neuronal loss in traumatic brain injury via innate immune activation.

    Dean, Terry / Mendiola, Andrew S / Yan, Zhaoqi / Meza-Acevedo, Rosa / Cabriga, Belinda / Akassoglou, Katerina / Ryu, Jae Kyu

    Journal of neuroinflammation

    2024  Volume 21, Issue 1, Page(s) 94

    Abstract: Background: Traumatic brain injury (TBI) causes significant blood-brain barrier (BBB) breakdown, resulting in the extravasation of blood proteins into the brain. The impact of blood proteins, especially fibrinogen, on inflammation and neurodegeneration ... ...

    Abstract Background: Traumatic brain injury (TBI) causes significant blood-brain barrier (BBB) breakdown, resulting in the extravasation of blood proteins into the brain. The impact of blood proteins, especially fibrinogen, on inflammation and neurodegeneration post-TBI is not fully understood, highlighting a critical gap in our comprehension of TBI pathology and its connection to innate immune activation.
    Methods: We combined vascular casting with 3D imaging of solvent-cleared organs (uDISCO) to study the spatial distribution of the blood coagulation protein fibrinogen in large, intact brain volumes and assessed the temporal regulation of the fibrin(ogen) deposition by immunohistochemistry in a murine model of TBI. Fibrin(ogen) deposition and innate immune cell markers were co-localized by immunohistochemistry in mouse and human brains after TBI. We assessed the role of fibrinogen in TBI using unbiased transcriptomics, flow cytometry and immunohistochemistry for innate immune and neuronal markers in Fgg
    Results: We show that cerebral fibrinogen deposits were associated with activated innate immune cells in both human and murine TBI. Genetic elimination of fibrin-CD11b interaction reduced peripheral monocyte recruitment and the activation of inflammatory and reactive oxygen species (ROS) gene pathways in microglia and macrophages after TBI. Blockade of the fibrin-CD11b interaction was also protective from oxidative stress damage and cortical loss after TBI.
    Conclusions: These data suggest that fibrinogen is a regulator of innate immune activation and neurodegeneration in TBI. Abrogating post-injury neuroinflammation by selective blockade of fibrin's inflammatory functions may have implications for long-term neurologic recovery following brain trauma.
    MeSH term(s) Humans ; Mice ; Animals ; Fibrin/genetics ; Fibrin/metabolism ; Brain Injuries, Traumatic/pathology ; Fibrinogen/metabolism ; Immunity, Innate ; Oxidative Stress ; Mice, Inbred C57BL
    Chemical Substances Fibrin (9001-31-4) ; Fibrinogen (9001-32-5)
    Language English
    Publishing date 2024-04-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2156455-3
    ISSN 1742-2094 ; 1742-2094
    ISSN (online) 1742-2094
    ISSN 1742-2094
    DOI 10.1186/s12974-024-03092-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Defining blood-induced microglia functions in neurodegeneration through multiomic profiling.

    Mendiola, Andrew S / Yan, Zhaoqi / Dixit, Karuna / Johnson, Jeffrey R / Bouhaddou, Mehdi / Meyer-Franke, Anke / Shin, Min-Gyoung / Yong, Yu / Agrawal, Ayushi / MacDonald, Eilidh / Muthukumar, Gayathri / Pearce, Clairice / Arun, Nikhita / Cabriga, Belinda / Meza-Acevedo, Rosa / Alzamora, Maria Del Pilar S / Zamvil, Scott S / Pico, Alexander R / Ryu, Jae Kyu /
    Krogan, Nevan J / Akassoglou, Katerina

    Nature immunology

    2023  Volume 24, Issue 7, Page(s) 1173–1187

    Abstract: Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. ... ...

    Abstract Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer's disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.
    MeSH term(s) Mice ; Animals ; Microglia/metabolism ; Multiomics ; Blood-Brain Barrier/metabolism ; Alzheimer Disease/genetics ; Fibrinogen
    Chemical Substances Fibrinogen (9001-32-5)
    Language English
    Publishing date 2023-06-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2016987-5
    ISSN 1529-2916 ; 1529-2908
    ISSN (online) 1529-2916
    ISSN 1529-2908
    DOI 10.1038/s41590-023-01522-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis.

    Petersen, Mark A / Tognatta, Reshmi / Meyer-Franke, Anke / Bushong, Eric A / Mendiola, Andrew S / Yan, Zhaoqi / Muthusamy, Abinaya / Merlini, Mario / Meza-Acevedo, Rosa / Cabriga, Belinda / Zhou, Yungui / Thomas, Reuben / Ryu, Jae Kyu / Lassmann, Hans / Ellisman, Mark H / Akassoglou, Katerina

    Brain : a journal of neurology

    2021  Volume 144, Issue 8, Page(s) 2291–2301

    Abstract: Extrinsic inhibitors at sites of blood-brain barrier disruption and neurovascular damage contribute to remyelination failure in neurological diseases. However, therapies to overcome the extrinsic inhibition of remyelination are not widely available and ... ...

    Abstract Extrinsic inhibitors at sites of blood-brain barrier disruption and neurovascular damage contribute to remyelination failure in neurological diseases. However, therapies to overcome the extrinsic inhibition of remyelination are not widely available and the dynamics of glial progenitor niche remodelling at sites of neurovascular dysfunction are largely unknown. By integrating in vivo two-photon imaging co-registered with electron microscopy and transcriptomics in chronic neuroinflammatory lesions, we found that oligodendrocyte precursor cells clustered perivascularly at sites of limited remyelination with deposition of fibrinogen, a blood coagulation factor abundantly deposited in multiple sclerosis lesions. By developing a screen (OPC-X-screen) to identify compounds that promote remyelination in the presence of extrinsic inhibitors, we showed that known promyelinating drugs did not rescue the extrinsic inhibition of remyelination by fibrinogen. In contrast, bone morphogenetic protein type I receptor blockade rescued the inhibitory fibrinogen effects and restored a promyelinating progenitor niche by promoting myelinating oligodendrocytes, while suppressing astrocyte cell fate, with potent therapeutic effects in chronic models of multiple sclerosis. Thus, abortive oligodendrocyte precursor cell differentiation by fibrinogen is refractory to known promyelinating compounds, suggesting that blockade of the bone morphogenetic protein signalling pathway may enhance remyelinating efficacy by overcoming extrinsic inhibition in neuroinflammatory lesions with vascular damage.
    MeSH term(s) Animals ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Bone Morphogenetic Protein Receptors/antagonists & inhibitors ; Bone Morphogenetic Proteins/metabolism ; Cell Differentiation/drug effects ; Homeostasis/drug effects ; Mice ; Mice, Transgenic ; Myelin Sheath/drug effects ; Myelin Sheath/metabolism ; Oligodendrocyte Precursor Cells/drug effects ; Oligodendrocyte Precursor Cells/metabolism ; Oligodendroglia/drug effects ; Oligodendroglia/metabolism ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; Quinolines/pharmacology ; Remyelination/drug effects ; Spinal Cord/drug effects ; Spinal Cord/metabolism
    Chemical Substances Bone Morphogenetic Proteins ; LDN-212854 ; Pyrazoles ; Pyrimidines ; Quinolines ; Bone Morphogenetic Protein Receptors (EC 2.7.11.30)
    Language English
    Publishing date 2021-08-23
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awab106
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  4. Article ; Online: Microglial G

    Merlini, Mario / Rafalski, Victoria A / Ma, Keran / Kim, Keun-Young / Bushong, Eric A / Rios Coronado, Pamela E / Yan, Zhaoqi / Mendiola, Andrew S / Sozmen, Elif G / Ryu, Jae Kyu / Haberl, Matthias G / Madany, Matthew / Sampson, Daniel Naranjo / Petersen, Mark A / Bardehle, Sophia / Tognatta, Reshmi / Dean, Terry / Acevedo, Rosa Meza / Cabriga, Belinda /
    Thomas, Reuben / Coughlin, Shaun R / Ellisman, Mark H / Palop, Jorge J / Akassoglou, Katerina

    Nature neuroscience

    2020  Volume 24, Issue 1, Page(s) 19–23

    Abstract: Microglial surveillance is a key feature of brain physiology and disease. Here, we found that ... ...

    Abstract Microglial surveillance is a key feature of brain physiology and disease. Here, we found that G
    MeSH term(s) Animals ; Calcium Signaling ; Cell Movement ; Convulsants ; Electroencephalography ; G-Protein-Coupled Receptor Kinase 1/physiology ; Immunologic Surveillance ; Mice ; Microglia/enzymology ; Microglia/physiology ; Microglia/ultrastructure ; Nerve Net/physiology ; Nervous System Diseases/physiopathology ; Nervous System Physiological Phenomena ; Pilocarpine ; Seizures/physiopathology ; Signal Transduction ; rho GTP-Binding Proteins/metabolism
    Chemical Substances Convulsants ; Pilocarpine (01MI4Q9DI3) ; G-Protein-Coupled Receptor Kinase 1 (EC 2.7.11.14) ; Grk1 protein, mouse (EC 2.7.11.14) ; rho GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2020-12-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1420596-8
    ISSN 1546-1726 ; 1097-6256
    ISSN (online) 1546-1726
    ISSN 1097-6256
    DOI 10.1038/s41593-020-00756-7
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  5. Article ; Online: Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk.

    Walsh, Kyle M / Codd, Veryan / Smirnov, Ivan V / Rice, Terri / Decker, Paul A / Hansen, Helen M / Kollmeyer, Thomas / Kosel, Matthew L / Molinaro, Annette M / McCoy, Lucie S / Bracci, Paige M / Cabriga, Belinda S / Pekmezci, Melike / Zheng, Shichun / Wiemels, Joseph L / Pico, Alexander R / Tihan, Tarik / Berger, Mitchell S / Chang, Susan M /
    Prados, Michael D / Lachance, Daniel H / O'Neill, Brian Patrick / Sicotte, Hugues / Eckel-Passow, Jeanette E / van der Harst, Pim / Wiencke, John K / Samani, Nilesh J / Jenkins, Robert B / Wrensch, Margaret R

    Nature genetics

    2014  Volume 46, Issue 7, Page(s) 731–735

    Abstract: Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of ... ...

    Abstract Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.
    MeSH term(s) Adult ; Case-Control Studies ; Genome-Wide Association Study ; Genotype ; Glioma/genetics ; Glioma/pathology ; Humans ; Leukocytes/metabolism ; Leukocytes/pathology ; Neoplasm Grading ; Polymorphism, Single Nucleotide/genetics ; Prognosis ; RNA/genetics ; Risk Factors ; Telomerase/genetics ; Telomere/genetics
    Chemical Substances telomerase RNA ; RNA (63231-63-0) ; TERT protein, human (EC 2.7.7.49) ; Telomerase (EC 2.7.7.49)
    Language English
    Publishing date 2014-06-08
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.3004
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