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      Debris clearance by microglia: an essential link between degeneration and regeneration

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          Abstract

          Microglia are cells of myeloid origin that populate the CNS during early development and form the brain's innate immune cell type. They perform homoeostatic activity in the normal CNS, a function associated with high motility of their ramified processes and their constant phagocytic clearance of cell debris. This debris clearance role is amplified in CNS injury, where there is frank loss of tissue and recruitment of microglia to the injured area. Recent evidence suggests that this phagocytic clearance following injury is more than simply tidying up, but instead plays a fundamental role in facilitating the reorganization of neuronal circuits and triggering repair. Insufficient clearance by microglia, prevalent in several neurodegenerative diseases and declining with ageing, is associated with an inadequate regenerative response. Thus, understanding the mechanism and functional significance of microglial-mediated clearance of tissue debris following injury may open up exciting new therapeutic avenues.

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          Most cited references 71

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          Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo.

          Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions. Furthermore, blood-brain barrier disruption provoked immediate and focal activation of microglia, switching their behavior from patroling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain.
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            Microglia-mediated neurotoxicity: uncovering the molecular mechanisms.

            Mounting evidence indicates that microglial activation contributes to neuronal damage in neurodegenerative diseases. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity. Pattern recognition receptors expressed on the microglial surface seem to be one of the primary, common pathways by which diverse toxin signals are transduced into ROS production. Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.
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              ATP mediates rapid microglial response to local brain injury in vivo.

               Wen-Biao Gan,  V. Kim,  Yi Zuo (2005)
              Parenchymal microglia are the principal immune cells of the brain. Time-lapse two-photon imaging of GFP-labeled microglia demonstrates that the fine termini of microglial processes are highly dynamic in the intact mouse cortex. Upon traumatic brain injury, microglial processes rapidly and autonomously converge on the site of injury without cell body movement, establishing a potential barrier between the healthy and injured tissue. This rapid chemotactic response can be mimicked by local injection of ATP and can be inhibited by the ATP-hydrolyzing enzyme apyrase or by blockers of G protein-coupled purinergic receptors and connexin channels, which are highly expressed in astrocytes. The baseline motility of microglial processes is also reduced significantly in the presence of apyrase and connexin channel inhibitors. Thus, extracellular ATP regulates microglial branch dynamics in the intact brain, and its release from the damaged tissue and surrounding astrocytes mediates a rapid microglial response towards injury.
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                Author and article information

                Journal
                Brain
                brainj
                brain
                Brain
                Oxford University Press
                0006-8950
                1460-2156
                February 2009
                20 June 2008
                20 June 2008
                : 132
                : 2
                : 288-295
                Affiliations
                1 Neural Regeneration, Institute of Reconstructive Neurobiology, University Bonn, Bonn, Germany 2 Department of Neurosurgery, Medical University Vienna, Vienna, Austria 3 Department of Neurosurgery, University of Göttingen, Göttingen, Germany 4 Department of Veterinary Medicine and Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK
                Author notes
                Correspondence to: Harald Neumann, Neural Regeneration, Institute of Reconstructive Neurobiology, University Bonn and Hertie-Foundation, Sigmund-Freud-Str. 25, 53127 Bonn, Germany E-mail: hneuman1@ 123456uni-bonn.de
                Article
                awn109
                10.1093/brain/awn109
                2640215
                18567623
                © 2008 The Author(s)

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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