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REMOVED: Identification of a unique molecular and functional microglia signature in health and disease
Abstracts / Int. J. Devl Neuroscience 47 (2015) 1–131
ISDN2014 0027
ISDN2014 0028
Identification of a unique molecular and functional microglia signature in health and disease
Targeting miR-155 restores dysfunctional microglia and ameliorates disease in the SOD1 model of ALS
Oleg Butovsky 1,∗ , Mark P. Jedrychowski 2 , Craig S. Moore 3 , Ron Cialic 1 , Amanda J. Lanser 1 , Galina Gabriely 1 , Thomas Koeglsperger 1 , Ben Dake 1 , Pauline M. Wu 1 , Camille E. Doykan 1 , Zain Fanek 1 , LiPing Liu 5 , Zhuoxun Chen 4 , Jeffrey D. Rothstein 4 , Richard M. Ransohoff 5 , Steven P. Gygi 2 , Jack P. Antel 3 , Howard L. Weiner 1
Oleg Butovsky 1,∗ , Mark P. Jedrychowski 2 , Ron Cialic 1 , Gopal Murugaiyan 1 , Pauline M. Wu 1 , Camille E. Doykan 1 , Zain Fanek 1 , David J. Greco 1 , Olga Kiner 1 , Robert J. Lawson 3 , Matthew P. Frosch 4 , Nathalie Pochet 5 , Anna M. Krichevsky 1 , Steven P. Gygi 2 , James Berry 3 , Merit E. Cudkowicz 3 , Howard L. Weiner 1
1 Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02112, USA 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA 3 Neuroimmunology Unit, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada 4 Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, MD, USA 5 Neuroinflammation Research Center, Cleveland Clinic, Cleveland, OH, USA
1 Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02112, USA 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA 3 Department of Neurology, Massachusetts General Hospital, Neurological Clinical Research Institute, Harvard Medical School, Boston, MA 02114, USA 4 Massachusetts General Hospital ADRC, Harvard University, Boston, MA, USA 5 Program in Translational NeuroPsychiatric Genomics, Brigham and Women’s Hospital, Harvard Medical School, Broad Institute of MIT and Harvard, USA
5
Microglia are resident macrophages of the central nervous system (CNS) that participate both in normal CNS function and disease. We identified a unique molecular and functional signature in microglia. This signature was not observed in microglial lines, peripheral macrophages or in monocytes recruited to the CNS and was also observed in human microglia. Based on this signature, we generated novel microglial surface specific antibodies and identified novel targets in resident microglia that can serve as therapeutic targets. We also identified unique patterns of microglia dysfunction associated with CNS disease in animal models of EAE, ALS and AD. Moreover, we found a crucial role for TGF-1 in microglial biology that included: (1) the requirement of TGF-1 for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia and (2) the absence of microglia in CNS TGF-1 deficient mice. Our results identify a unique microglial signature that is dependent on TGF- signalling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. In the SOD1 model of ALS we found loss of the unique molecular signature that characterizes microglia in association with increased expression of miR-155. There was loss of unique microglial molecules P2ry12, Tmem119, Olfml3, microglial transcription factors Egr1, Atf3, Jun, Fos, Mafb and upstream regulators Csf1r, Tgfb1 and Tgfbr1 essential for microglial survival. Major microglia biological functions including phagocytosis were suppressed. Genetic ablation of miR-155 increased survival in SOD1 mice and reversed abnormal microglial and monocyte molecular signatures. We found increased expression of miR-155 in the spinal cord of ALS subjects. Dysregulated proteins in SOD1 spinal cord that we identified in human ALS spinal cord and CSF were restored in SOD1G93A /miR-155−/− mice. Treatment with anti-miR-155 injected systemically or into the CSF prolonged survival and derepressed microglial miR-155 targeted genes. Our findings identify a new avenue for immune based therapy of ALS by targeting miR-155.
http://dx.doi.org/10.1016/j.ijdevneu.2015.04.022
http://dx.doi.org/10.1016/j.ijdevneu.2015.04.023 ISDN2014 0029 Evidence for a decrease in dendrites of pyramidal cells in neonatal thalamic lesioned rat’s prefrontal cortex: Implication in Autism and Schizophrenia Z. Ouhaz ∗ , S. Ba M’hamed, M. Bennis Lab of Pharmacology, Neurobiology & Behavior (URAC-37), Cadi Ayyad University, Marrakech, Morocco Many developmental disorders such as Autism and Schizophrenia involve both cortical and subcortical structures, our central hypothesis, is that some of the abnormalities in cerebral cortex structure and function that underlie developmental disorders result from an early insult to the thalamus, which in turn leads to maldevelopment of the cerebral cortex.
ISDN2014 0027
ISDN2014 0028
Identification of a unique molecular and functional microglia signature in health and disease
Targeting miR-155 restores dysfunctional microglia and ameliorates disease in the SOD1 model of ALS
Oleg Butovsky 1,∗ , Mark P. Jedrychowski 2 , Craig S. Moore 3 , Ron Cialic 1 , Amanda J. Lanser 1 , Galina Gabriely 1 , Thomas Koeglsperger 1 , Ben Dake 1 , Pauline M. Wu 1 , Camille E. Doykan 1 , Zain Fanek 1 , LiPing Liu 5 , Zhuoxun Chen 4 , Jeffrey D. Rothstein 4 , Richard M. Ransohoff 5 , Steven P. Gygi 2 , Jack P. Antel 3 , Howard L. Weiner 1
Oleg Butovsky 1,∗ , Mark P. Jedrychowski 2 , Ron Cialic 1 , Gopal Murugaiyan 1 , Pauline M. Wu 1 , Camille E. Doykan 1 , Zain Fanek 1 , David J. Greco 1 , Olga Kiner 1 , Robert J. Lawson 3 , Matthew P. Frosch 4 , Nathalie Pochet 5 , Anna M. Krichevsky 1 , Steven P. Gygi 2 , James Berry 3 , Merit E. Cudkowicz 3 , Howard L. Weiner 1
1 Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02112, USA 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA 3 Neuroimmunology Unit, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada 4 Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, MD, USA 5 Neuroinflammation Research Center, Cleveland Clinic, Cleveland, OH, USA
1 Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02112, USA 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA 3 Department of Neurology, Massachusetts General Hospital, Neurological Clinical Research Institute, Harvard Medical School, Boston, MA 02114, USA 4 Massachusetts General Hospital ADRC, Harvard University, Boston, MA, USA 5 Program in Translational NeuroPsychiatric Genomics, Brigham and Women’s Hospital, Harvard Medical School, Broad Institute of MIT and Harvard, USA
5
Microglia are resident macrophages of the central nervous system (CNS) that participate both in normal CNS function and disease. We identified a unique molecular and functional signature in microglia. This signature was not observed in microglial lines, peripheral macrophages or in monocytes recruited to the CNS and was also observed in human microglia. Based on this signature, we generated novel microglial surface specific antibodies and identified novel targets in resident microglia that can serve as therapeutic targets. We also identified unique patterns of microglia dysfunction associated with CNS disease in animal models of EAE, ALS and AD. Moreover, we found a crucial role for TGF-1 in microglial biology that included: (1) the requirement of TGF-1 for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia and (2) the absence of microglia in CNS TGF-1 deficient mice. Our results identify a unique microglial signature that is dependent on TGF- signalling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. In the SOD1 model of ALS we found loss of the unique molecular signature that characterizes microglia in association with increased expression of miR-155. There was loss of unique microglial molecules P2ry12, Tmem119, Olfml3, microglial transcription factors Egr1, Atf3, Jun, Fos, Mafb and upstream regulators Csf1r, Tgfb1 and Tgfbr1 essential for microglial survival. Major microglia biological functions including phagocytosis were suppressed. Genetic ablation of miR-155 increased survival in SOD1 mice and reversed abnormal microglial and monocyte molecular signatures. We found increased expression of miR-155 in the spinal cord of ALS subjects. Dysregulated proteins in SOD1 spinal cord that we identified in human ALS spinal cord and CSF were restored in SOD1G93A /miR-155−/− mice. Treatment with anti-miR-155 injected systemically or into the CSF prolonged survival and derepressed microglial miR-155 targeted genes. Our findings identify a new avenue for immune based therapy of ALS by targeting miR-155.
http://dx.doi.org/10.1016/j.ijdevneu.2015.04.022
http://dx.doi.org/10.1016/j.ijdevneu.2015.04.023 ISDN2014 0029 Evidence for a decrease in dendrites of pyramidal cells in neonatal thalamic lesioned rat’s prefrontal cortex: Implication in Autism and Schizophrenia Z. Ouhaz ∗ , S. Ba M’hamed, M. Bennis Lab of Pharmacology, Neurobiology & Behavior (URAC-37), Cadi Ayyad University, Marrakech, Morocco Many developmental disorders such as Autism and Schizophrenia involve both cortical and subcortical structures, our central hypothesis, is that some of the abnormalities in cerebral cortex structure and function that underlie developmental disorders result from an early insult to the thalamus, which in turn leads to maldevelopment of the cerebral cortex.