Deleterious effects of lymphocytes at the early stage of neurodegeneration in an animal model of amyotrophic lateral sclerosis

Satoru Tada,Tomoyuki Sugimoto,Hitoshi Kikutani,Teruhito Yasui,Tatsusada Okuno,Yuji Nakatsuji,Saburo Sakoda

doi:10.1186/1742-2094-8-19

Satoru Tada, Tomoyuki Sugimoto + Show 5 more

Open Access

https://doi.org/10.1186/1742-2094-8-19

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Abstract

BackgroundNon-neuronal cells, such as microglia and lymphocytes, are thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Previous studies have demonstrated neuroprotective effects of lymphocytes at the end stage of ALS, partly through induction of alternatively activated microglia (M2 microglia), which are neuroprotective. In this study, we investigated the role of lymphocytes in the early stage of the disease using an animal model of inherited ALS.MethodsWe established a transgenic mouse line overexpressing the familial ALS-associated G93A-SOD1 mutation (harboring a single amino acid substitution of glycine to alanine at codon 93) with depletion of the Rag2 gene (mSOD1/RAG2-/- mice), an animal model of inherited ALS lacking mature lymphocytes. Body weights, clinical scores and motor performance (hanging wire test) of mSOD1/RAG2-/- mice were compared to those of mutant human SOD1 transgenic mice (mSOD1/RAG2+/+ mice). Activation of glial cells in the spinal cords of these mice was determined immunohistochemically, and the expression of mRNA for various inflammatory and anti-inflammatory molecules was evaluated.ResultsClinical onset in mSOD1/RAG2-/- mice was significantly delayed, and the number of lectin-positive cells in spinal cord was increased at the early stage of disease when compared to mSOD1/RAG2+/+ mice. Quantitative RT-PCR confirmed that mRNA for Ym1, an M2 microglial-related molecule, was significantly increased in mSOD1/RAG2-/- mouse spinal cords at the early disease stage.ConclusionsCompared with mSOD1/RAG2+/+ mice, mSOD1/RAG2-/- mice displayed delayed onset and increased M2 microglial activation at the early stage of disease. Thus, lymphocytes at the early pathological phase of ALS display a deleterious effect via inhibition of M2 microglial activation.

Highlights

Non-neuronal cells, such as microglia and lymphocytes, are thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS)
ALS is characterized by motor neuron degeneration, activation of microglia and astrocytes and infiltration of T lymphocytes are significant pathological hallmarks in the spinal cord lesions of ALS patients and mSOD1 mice, and a role for these cells in the pathogenesis of ALS has been suggested [4,5,6]
To determine if delayed onset in mSOD1/RAG2-/- mice is attributable to increased numbers of M2 microglia, we evaluated the mRNA expression of M2 microglial target genes in spinal cord of mSOD1/RAG2-/- mice and control mice

Summary

Introduction

Non-neuronal cells, such as microglia and lymphocytes, are thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degeneration of motor neurons in brain and the spinal cord, resulting in muscle weakness. ALS is characterized by motor neuron degeneration, activation of microglia and astrocytes and infiltration of T lymphocytes are significant pathological hallmarks in the spinal cord lesions of ALS patients and mSOD1 mice, and a role for these cells in the pathogenesis of ALS has been suggested [4,5,6]. Representative T helper 2 (Th2) cytokines, such as interleukin 4 (IL-4) and interleukin 13 (IL-13), can convert microglia, primed by macrophage colony-stimulating factor (M-CSF), to an alternatively activated M2 phenotype [12]. The precise roles of crosstalk between T cells and microglia in the pathology of ALS remain unknown

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