Elsevier

The Lancet Neurology

Volume 10, Issue 3, March 2011, Pages 253-263
The Lancet Neurology

Review
Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease

https://doi.org/10.1016/S1474-4422(11)70015-1Get rights and content

Summary

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) are characterised by the appearance of reactive microglial and astroglial cells, a process referred to as neuroinflammation. In transgenic mouse models of mutant SOD1-associated familial ALS, reactive microglial cells and astrocytes actively contribute to the death of motor neurons. The biological processes that drive this glial reaction are complex and have both beneficial and deleterious effects on motor neurons. Therapeutic interventions targeting these cells are being explored. An improved understanding of the biological processes that cause neuroinflammation will help to define its medical importance and to identify the therapeutic potential of interfering with this reaction.

Introduction

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) represent a biomedical challenge; their frequent occurrence in the growing population of elderly people has become a concern for western health-care systems. Identification of strategies for treatment of these disorders is an important task for translational neuroscience. ALS is a degenerative disorder, mainly but not exclusively affecting the motor neurons in the spinal cord, brainstem, and cortex. This degeneration results in fasciculations, muscle weakness and muscle atrophy, and hyper-reflexia with spasticity. Although the course of ALS is variable, median survival of patients is less than 3 years. A minority of patients with ALS have concomitant frontotemporal dementia, but more subtle frontal executive difficulties occur in many.1

The disease is familial in 10% of patients and is usually characterised by a dominant pattern of inheritance. Several ALS-causing genes (in familial ALS) or ALS-associated genes (in sporadic and familial ALS) have been identified.2 Mutations in SOD1 are by far the most common cause of familial ALS (20%), whereas mutations in TARDBP (5%), FUS (5%), and ANG (<1%) are less common. VCP3 and OPTN4 mutations have been recently added to the steadily growing list of genes associated with ALS. Mice and rats that overexpress the human mutant superoxide dismutase 1 (SOD1) protein are used extensively to study ALS;5, 6 they develop adult-onset, progressive, and ultimately fatal muscle weakness and atrophy, caused by prominent motor-neuron degeneration. Mice and rats with mutant forms of TAR DNA binding protein 43 (TDP-43) have become available only recently.7, 8 The cause of sporadic ALS remains unknown and no reliable animal model for this form of the disease is available. Conformational changes similar to those in mutant SOD1 have been seen in wild-type SOD1 from samples of spinal cord from patients with sporadic ALS, suggesting that modified wild-type SOD1 could contribute to its pathogenic mechanism.9 Of note, most patients with sporadic ALS have TDP-43-containing inclusions in their motor neurons, despite not harbouring mutations in this protein.10 Findings from studies of familial ALS (in humans and in animal models) are likely to be relevant to studies of sporadic ALS.

A common characteristic of ALS and other neurodegenerative disorders is the occurrence of a neuroinflammatory reaction consisting of activated glial cells, mainly microglia and astrocytes, and T cells. This inflammatory reaction has recently received attention as an unexpected potential target for the treatment of these diseases. For ALS, knowledge of the contribution of microglia, astrocytes, and inflammatory T cells to the degeneration of motor neurons has expanded greatly, and has resulted in clinical trials of drugs targeting neuroinflammatory processes in patients with ALS. In this Review, we attempt to address the clinical importance of this neuroinflammatory response in patients with ALS.

Section snippets

Key players in neuroinflammation

Microglia are of mesenchymal origin and are the resident macrophages in the nervous system; they constantly monitor the extracellular environment, closely interact with astrocytes and neurons, and can be identified as ramified CD11b (also known as ITGAM) expressing cells. Microglia are activated by a range of signals,11 and are the first line of defence against infection or injury to the nervous system. Although the microglial response is diverse, generally, upon activation, microglia acquire

Glial activation in ALS

Many studies have characterised the activation of microglia and astrocytes, and the appearance of lymphocytes in post-mortem tissue of patients with ALS and in the spinal cord of transgenic mice that express a mutant form of human SOD1.22, 23, 24, 25, 26, 27, 28, 29 Clear upregulation of expression of CD11b, IBA1 (ionised calcium-binding adapter molecule 1), and CD68 markers for microglia, and of GFAP and ALDH1L1 markers for astrocytes, is reported consistently. Additionally, these cells change

Effects of glial cells on motor-neuron degeneration

SOD1-mutant mice with motor-neuron degeneration express the transgene ubiquitously. Selective expression of mutant SOD1 in motor neurons did not result in loss of motor neurons48, 49 or gave rise to mild abnormalities only.50, 51 Selective expression in astrocytes or microglia did not result in motor-neuron degeneration either.52, 53 These studies provided evidence that expression in motor neurons is necessary, but that surrounding cells play an important part in motor-neuron degeneration. The

Factors that influence the neuroinflammatory response

A wide range of factors has been suggested to induce a neuroinflammatory response in patients with ALS and to mediate the hazardous and beneficial effects of glial cells on motor neurons.67 Chemokines such as chemokine (C-C) motif ligand 2 (CCL2) are greatly upregulated in spinal cords of SOD1-mutant mice and of patients with ALS.31, 32 Similarly, colony stimulating factor 1 (CSF1) is increased greatly in spinal cords of SOD1-mutant mice.68 These factors could contribute to the increased

From animal models to therapeutic strategies

Results from many studies investigating beneficial effects of immune-active or anti-inflammatory compounds, and of transplantation of myeloid (and astroglial) cells in mice and rats, have encouraged clinicians to explore the neuroinflammatory response in patients with ALS as a potential therapeutic target; so far, results of these studies have been disappointing. General immunosuppression or immunomodulation (using cyclophosphamide, ciclosporin, interferon beta, and many others) was reported to

Outstanding questions and future perpectives

Our understanding of neuroinflammation in mutant SOD1 models has improved greatly. What was thought of as a non-specific reaction has now emerged into an area of intense research, the results of which are relevant not only to motor-neuron degeneration, but to neurodegeneration and neurobiological processes generally. Additionally, the neuroinflammatory reaction creates opportunities for intervention. However, our understanding of neuroinflammation in ALS is far from complete. We mention only a

Search strategy and selection criteria for references

We searched Pubmed for published works using the following search terms: “microglia,” “astrocytes”, “inflammation”, “motor neuron degeneration”, and “amyotrophic lateral sclerosis”. Only reports published in English, between January, 1990, and December, 2010, that had clear in-vivo relevance, and had potential for translation into human beings were included.

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