A comparison of in vitro properties of resting SOD1 transgenic microglia reveals evidence of reduced neuroprotective function

BMC Neuroscience

Research Article

Peter N Monk¹  Siranush A Sargsyan²  Julian Grosskreutz³  Kurt J De Vos⁴  Siân C Barber⁵  Daniel J Blackburn⁵  Pamela J Shaw⁵ 

[1]Department of Infection and Immunity, School of Medicine and Biomedical Sciences, University of Sheffield, UK

[2]Department of Medicine, University of Colorado Denver School of Medicine, CO, USA

[3]Hans Berger Department of Neurology, University Hospital Jena, Jena, Germany

[4]MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK

[5]The Academic Neurology Unit, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, S10 2HQ, UK

关键词: Amyotrophic Lateral Sclerosis;    Mutant SOD1;    Amyotrophic Lateral Sclerosis Case;    SOD1 G93A;    Mixed Glial Culture;   

DOI  :  10.1186/1471-2202-12-91

 received in 2011-05-08, accepted in 2011-09-23,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundOverexpression 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.ResultsTG 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).ConclusionsThese 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.

【 授权许可】

CC BY   
© Sargsyan et al; licensee BioMed Central Ltd. 2011