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.
ReviewNeuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease
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
References (130)
- et al.
Exome sequencing reveals VCP mutations as a cause of familial ALS
Neuron
(2010) - et al.
The chemokine system in diverse forms of macrophage activation and polarization
Trends Immunol
(2004) - et al.
Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-beta
J Neuroimmunol
(2009) - et al.
Astrocytes are active players in cerebral innate immunity
Trends Immunol
(2007) - et al.
Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis
J Neurol Sci
(1996) - et al.
The chemokine MCP-1 and the dendritic and myeloid cells it attracts are increased in the mSOD1 mouse model of ALS
Mol Cell Neurosci
(2006) - et al.
Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study
Neurobiol Dis
(2004) - et al.
Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS)
J Neuroimmunol
(2005) - et al.
Intra–bone marrow–bone marrow transplantation slows disease progression and prolongs survival in G93A mutant SOD1 transgenic mice, an animal model mouse for amyotrophic lateral sclerosis
Brain Res
(2009) - et al.
Selective ablation of proliferating astrocytes does not affect disease outcome in either acute or chronic models of motor neuron degeneration
Exp Neurol
(2008)
NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration
Neuron
Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology
Neurobiol Dis
Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease
Neuron
T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening?
Trends Immunol
The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis
Neurobiol Dis
Mechanisms underlying inflammation in neurodegeneration
Cell
Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis
Brain Res Mol Brain Res
Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase
Exp Neurol
Circulating levels of tumour necrosis factor-alpha and its soluble receptors are increased in the blood of patients with amyotrophic lateral sclerosis
Neurosci Lett
Motoneuron death triggered by a specific pathway downstream of Fas. potentiation by ALS-linked SOD1 mutations
Neuron
Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis
Exp Neurol
Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis
Neurobiol Dis
Prevalence and patterns of cognitive impairment in sporadic ALS
Neurology
Recent advances in motor neuron disease
Curr Opin Neurol
Mutations of optineurin in amyotrophic lateral sclerosis
Nature
Transgenic-mouse model of amyotrophic lateral sclerosis
N Engl J Med
Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: associated mutations develop motor neuron disease
J Neurosci
TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration
Proc Natl Acad Sci USA
Transgenic rat model of neurodegeneration caused by mutation in the TDP gene
PLoS Genet
Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS
Nat Neurosci
Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies
Acta Neuropathol
Microglia: active sensor and versatile effector cells in the normal and pathologic brain
Nat Neurosci
Microglia in ALS: the good, the bad, and the resting
J Neuroimmune Pharmacol
Astrocytes: biology and pathology
Acta Neuropathol
T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS
Proc Natl Acad Sci USA
CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS
Proc Natl Acad Sci USA
PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice
Nat Neurosci
NG2 cells generate oligodendrocytes and gray matter astrocytes in the spinal cord
Neuron Glia Biol
Motor neuron degeneration promotes neural progenitor cell proliferation, migration, and neurogenesis in the spinal cords of amyotrophic lateral sclerosis mice
Stem Cells
IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis
Arch Neurol
Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis
Arch Neurol
Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS
Glia
Immune reactivity in a mouse model of familial ALS correlates with disease progression
Neurology
Reactive astrocytes are widespread in the cortical gray matter of amyotrophic lateral sclerosis
J Neurosci Res
Reactive astrogliosis is widespread in the subcortical white matter of amyotrophic lateral sclerosis brain
J Neuropathol Exp Neurol
Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue
Am J Pathol
Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase
J Neurosci
Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue
Ann Neurol
Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS)
Glia
Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice
Proc Natl Acad Sci USA
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