Lewis, KE and Rasmussen, AL and Bennett, W and King, A and West, AK and Chung, RS and Chuah, MI, Microglia and motor neurons during disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis: Changes in arginase1 and inducible nitric oxide synthase, Journal of Neuroinflammation, 11 Article 55. ISSN 1742-2094 (2014) [Refereed Article]
Licensed under Creative Commons Attribution 2.0 Generic (CC BY 2.0) http://creativecommons.org/licenses/by/2.0/
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the motor system. Although the etiology of the disease is not fully understood, microglial activation and neuroinflammation are thought to play a role in disease progression.
Methods: We examined the immunohistochemical expression of two markers of microglial phenotype, the arginine-metabolizing enzymes inducible nitric oxide synthase (iNOS) and arginase1 (Arg1), in the spinal cord of a mouse model carrying an ALS-linked mutant human superoxide dismutase transgene (SOD1G93A) and in non-transgenic wild-type (WT) mice. Immunolabeling for iNOS and Arg1 was evaluated throughout disease progression (6 to 25 weeks), and correlated with body weight, stride pattern, wire hang duration and ubiquitin pathology. For microglia and motor neuron counts at each time point, SOD1G93A and WT animals were compared using an independent samples t-test. A Welch t-test correction was applied if Levene’s test showed that the variance in WT and SOD1G93A measurements was substantially different.
Results: Disease onset, measured as the earliest change in functional parameters compared to non-transgenic WT mice, occurred at 14 weeks of age in SOD1G93A mice. The ventral horn of the SOD1G93A spinal cord contained more microglia than WT from 14 weeks onwards. In SOD1G93A mice, Arg1-positive and iNOS-positive microglia increased 18-fold and 7-fold, respectively, between 10 and 25 weeks of age (endpoint) in the lumbar spinal cord, while no increase was observed in WT mice. An increasing trend of Arg1- and iNOS-expressing microglia was observed in the cervical spinal cords of SOD1G93A mice. Additionally, Arg1-negative motor neurons appeared to selectively decline in the spinal cord of SOD1G93A mice, suggesting that Arg1 may have a neuroprotective function.
Conclusions: This study suggests that the increase in spinal cord microglia occurs around and after disease onset and is preceded by cellular pathology. The results show that Arg1 and iNOS, thought to have opposing inflammatory properties, are upregulated in microglia during disease progression and that Arg1 in motor neurons may confer protection from disease processes. Further understanding of the neuroinflammatory response, and the Arg1/iNOS balance in motor neurons, may provide suitable therapeutic targets for ALS.
|Item Type:||Refereed Article|
|Keywords:||amyotrophic lateral sclerosis, microglia, inducible nitric oxide synthase, arginase1, motor neurons, lumbar spinal cord, cervical spinal cord, neuroinflammation|
|Research Division:||Medical and Health Sciences|
|Research Field:||Cellular Nervous System|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Nervous System and Disorders|
|Author:||Lewis, KE (Dr Katherine Lewis)|
|Author:||Rasmussen, AL (Ms Anna Rasmussen)|
|Author:||Bennett, W (Dr Bill Bennett)|
|Author:||King, A (Associate Professor Anna King)|
|Author:||West, AK (Professor Adrian West)|
|Author:||Chung, RS (Associate Professor Roger Chung)|
|Author:||Chuah, MI (Dr Inn Chuah)|
|Web of Science® Times Cited:||18|
|Deposited By:||Wicking Dementia Research and Education Centre|
|Downloads:||246 View Download Statistics|
Repository Staff Only: item control page