Sargsyan, S.A., Blackburn, D.J., Barber, S.C. et al. (4 more authors) (2011) A comparison of in vitro properties of resting SOD1 transgenic microglia reveals evidence of reduced neuroprotective function. BMC Neuroscience, 12. 91. ISSN 1471-2202
Abstract
Background
Overexpression of mutant copper/zinc superoxide dismutase (SOD1) in rodents has provided useful models for studying the pathogenesis of amyotrophic lateral sclerosis (ALS). Microglia have been shown to contribute to ALS disease progression in these models, although the mechanism of this contribution remains to be elucidated. Here, we present the first evidence of the effects of overexpression of mutant (TG G93A) and wild type (TG WT) human SOD1 transgenes on a set of functional properties of microglia relevant to ALS progression, including expression of integrin β-1, spreading and migration, phagocytosis of apoptotic neuronal cell debris, and intracellular calcium changes in response to an inflammatory stimulus.
Results
TG SOD1 G93A but not TG SOD1 WT microglia had lower expression levels of the cell adhesion molecule subunit integrin β-1 than their NTG control cells [NTG (G93A) and NTG (WT), respectively, 92.8 ± 2.8% on TG G93A, 92.0 ± 6.6% on TG WT, 100.0 ± 1.6% on NTG (G93A), and 100.0 ± 2.7% on NTG (WT) cells], resulting in decreased spreading ability, with no effect on ability to migrate. Both TG G93A and TG WT microglia had reduced capacity to phagocytose apoptotic neuronal cell debris (13.0 ± 1.3% for TG G93A, 16.5 ± 1.9% for TG WT, 28.6 ± 1.8% for NTG (G93A), and 26.9 ± 2.8% for NTG (WT) cells). Extracellular stimulation of microglia with ATP resulted in smaller increase in intracellular free calcium in TG G93A and TG WT microglia relative to NTG controls (0.28 ± 0.02 μM for TG G93A, 0.24 ± 0.03 μM for TG WT, 0.39 ± 0.03 μM for NTG (G93A), and 0.37 ± 0.05 μM for NTG (WT) microglia).
Conclusions
These findings indicate that, under resting conditions, microglia from mutant SOD1 transgenic mice have a reduced capacity to elicit physiological responses following tissue disturbances and that higher levels of stimulatory signals, and/or prolonged stimulation may be necessary to initiate these responses. Overall, resting mutant SOD1-overexpressing microglia may have reduced capacity to function as sensors of disturbed tissue/cellular homeostasis in the CNS and thus have reduced neuroprotective function.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2011 Sargsyan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | AMYOTROPHIC-LATERAL-SCLEROSIS; CENTRAL-NERVOUS-SYSTEM; CU/ZN-SUPEROXIDE-DISMUTASE; MOTOR-NEURON DEGENERATION; NECROSIS-FACTOR-ALPHA; SPINAL-CORD TISSUE; DOWNS-SYNDROME; MOUSE MODEL; EXTEND SURVIVAL; ANIMAL-MODEL |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection and Immunity (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 25 Nov 2014 16:22 |
Last Modified: | 25 Nov 2014 16:22 |
Published Version: | http://dx.doi.org/10.1186/1471-2202-12-91 |
Status: | Published |
Publisher: | Biomed Central |
Refereed: | Yes |
Identification Number: | 10.1186/1471-2202-12-91 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:81867 |