Elsevier

Brain Research Reviews

Volume 47, Issues 1–3, December 2004, Pages 263-274
Brain Research Reviews

Review
A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis

https://doi.org/10.1016/j.brainresrev.2004.05.003Get rights and content

Abstract

A strong glial reaction typically surrounds the affected upper and lower motor neurons and degenerating descending tracts of ALS patients. Reactive astrocytes in ALS contain protein inclusions, express inflammatory makers such as the inducible forms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), display nitrotyrosine immunoreactivity and downregulate the glutamate transporter EAAT2. In this review, we discuss the evidence sustaining an active role for astrocytes in the induction and propagation of motor neuron loss in ALS. Available evidence supports the view that glial activation could be initiated by proinflammatory mediators secreted by motor neurons in response to injury, axotomy or muscular pathology. In turn, reactive astrocytes produce nitric oxide and peroxynitrite, which cause mitochondrial damage in cultured neurons and trigger apoptosis in motor neurons. Astrocytes may also contribute to the excitotoxic damage of motor neurons by decreasing glutamate transport or actively releasing the excitotoxic amino acid. In addition, reactive astrocytes secrete pro-apoptotic mediators, such as nerve growth factor (NGF) or Fas-ligand, a mechanism that may serve to eliminate vulnerable motor neurons. The comprehensive understanding of the interactions between motor neurons and glia in ALS may lead to a more accurate theory of the pathogenesis of the disease.

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease originally described by Charcot in 1869, characterized by the selective degeneration of motor neurons from the cortex, brainstem and spinal cord that leads to progressive paralysis and muscle atrophy. Most hypotheses for this selective cell loss have primarily addressed early changes in motor neurons involving oxidative damage, defective cytoskeletal function, protein misfolding and aggregation and excitotoxicity from disruption of extracellular glutamate homeostasis. The degeneration of motor neurons is so blatant that it tends to obscure subtle changes in other cell types that may contribute to ALS. In this review, we will consider the origin of reactive astrogliosis in ALS and how reactive changes in astrocytes may contribute to the progressive nature of ALS.

About 10% of ALS cases show familial inheritance, 20% of which are caused by mutations in the gene encoding copper, zinc superoxide dismutase (SOD-1) [106]. An important clue to the pathogenesis of ALS was provided by the development of several strains of different transgenic animal models of the disease carrying the expression of high levels of mutated SOD-1 genes. Toxicity of mutant SOD-1 involves a dominant gain-of-function rather than simply diminished superoxide-scavenging activity [12], [24], [54]. Spinal motor neurons express high levels of mutant SOD-1 which might explain the selective vulnerability of these neurons. However, current evidence indicates that ALS-linked SOD-1 mutations must be expressed in both neuronal and non-neuronal cells to induce the disease [52], [96]. These findings suggest that interactions between motor neurons and surrounding cells in the spinal cord, nerve or skeletal muscle are required for mutated SOD-1 to initiate neurodegeneration in ALS. Accordingly, a recent study by Clement et al. [23] using chimeric mice composed of mixtures of normal cells and cells expressing ALS mutant SOD-1 showed that motor neuron degeneration is not necessarily associated with the expression of SOD-1 mutations in the motor neuron per se but rather with its expression in a critical number of neighboring neuronal and non-neuronal cells.

Astrocytes represent the largest cell population in the central nervous system (CNS). They closely interact with neurons to provide structural, metabolic and trophic support and actively participate in modulating neuronal excitability and neurotransmission by controlling the extracellular levels of ions and neurotransmitters [13], [41]. In vitro, astrocytes exert potent trophic influences on motor neurons [4], [32], [94] through a variety of proteins and low molecular weight molecules [113], [122], which can be modulated by neuroprotective drugs [94]. In response to injury, astrocytes and microglia display characteristic phenotypic changes characterized as astrocytosis or gliosis. Astrocytes respond to CNS damage by proliferating and adopting a reactive phenotype characterized morphologically by hypertrophic nuclei and cell bodies and elaboration of distinct long and thick processes with increased content of glial fibrillary acidic protein (GFAP). In addition, reactive astrocytes express a wide variety of markers such as cytoskeleton proteins, cell surface and matrix molecules, proteases, protease inhibitors and several growth factors and cytokines [31], [104]. By secreting diffusible factors, damaged neurons or activated astrocytes interact in a complex manner with immune cells and microglia. Activated microglia, in turn, secrete proinflammatory peptides, nitric oxide (NO) and excitotoxins that induce astrocytosis or aggravate neuronal damage, therefore, perpetuating and amplifying a local pathogenic process [51]. However, subtler states of microglia activation may lead to downregulation of the neuroinflammatory process. Since gliosis also occurs in a variety of conditions such as cerebral ischemia, Alzheimer's disease, Parkinson's disease, frontotemporal dementia and Huntington's disease [120], it has long been suggested to be a non-specific response of glial cells to injury and often it is not considered as a primary pathogenic element in ALS. On the other hand, recent evidence indicates the existence of other molecular mechanisms by which activated astrocytes may contribute to either the death of neurons or to their survival in response to damage. Extensive reviews have been recently published about the pathogenesis of ALS [12], [25], [110], the role of microglia and inflammatory cells in ALS [83], and the immune function of astrocytes [31]. In this review, we examine the current evidence that supports an active role of astrocytes contributing both to the induction and to the propagation of motor neuron loss. Understanding of the interactions between neurons and glia in ALS may help to explain the progressive nature of ALS.

Section snippets

Astrocyte pathology in ALS

A strong glial reaction typically surrounds both upper and lower motor neurons in ALS patients [59], [71], [87], [90], [120]. Some degree of gliosis is also found in the lateral descending corticospinal tracts and in the entering points of the tracts into the gray matter [118], thus forming a continuum along the damaged regions. Microglia also proliferate and become activated in these regions, and invading T cells can be found around the capillaries [83]. Reactive astrocytes in ALS show

The origin of astrocytosis in ALS

Symptomatic ALS mice develop a typical “isomorphic” gliosis characterized by proliferative, hypertrophic and globular astrocytes [104]. This type of gliosis has also been described after CNS trauma, epilepsy or axotomy and is mediated by complex signaling between neurons, microglia and astrocytes [82]. However, astrocytes do not respond in a stereotypic manner to all forms of cell or tissue damage. The combination of different mediators such as cytokines, chemokines, growth factors and adhesion

Neurotoxic potential of reactive astrocytes in ALS

Recent studies have emphasized the involvement of astrocyte dysfunction in the pathogenesis of ALS through different synergistic mechanisms.

Astrocytes and motor neuron death

We hypothesize that oxidative stress, occurring in damaged areas undergoing neurodegeneration, disrupts the interactions between motor neuron and astrocytes (Fig. 1). In response to damage, motor neurons can signal the surrounding astrocytes to become activated and upregulate critical genes that may recapitulate the pattern found during development. For example, the re-expression of p75NTR and neuronal NOS may help to determine which neurons survive or undergo apoptosis. In turn, activated

Conclusions

The pathology of ALS is characterized by widespread signs of neuronal and astrocyte dysfunction which account for the appearance of protein aggregates, cytoskeletal abnormalities and mitochondrial swelling. These changes not only affect motor neurons but also the surrounding astrocytes and many interneurons. The origin of this pan-cellular pathology is intriguing and deserves further investigation. Because reactive astrocytes occurring in ALS may spread the phenotypic transformation to

Acknowledgements

This work was supported by the PEDECIBA program; the Linus Pauling Institute, the Environmental Health Sciences Center (ES0021) Oregon State University (USA) and grants from the National Institutes of Health R03 TW006482; P01AT002034; R01 NS033291. We thank Dr. Mark Bevensee for his insightful comments.

References (141)

  • V.L. Dawson et al.

    Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal glial cortical cultures

    Neuropharmacology

    (1994)
  • K.L. Eagleson et al.

    Motoneurone survival is induced by immature astrocytes from developing avian spinal cord

    Dev. Brain Res

    (1985)
  • M. Eddleston et al.

    Molecular profile of reactive astrocytes: implications for their role in neurologic disease

    Neuroscience

    (1993)
  • P. Ernfors et al.

    Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons

    Neuron

    (1989)
  • M. Fahnestock et al.

    Nerve growth factor mRNA and protein levels measured in the same tissue from normal and Alzheimer's disease parietal cortex

    Mol. Brain Res

    (1996)
  • M. Fahnestock et al.

    The precursor pro nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease

    Mol. Cell. Neurosci

    (2001)
  • K.M. Faulkner et al.

    Stable Mn(III) porphyrins mimic superoxide dismutase in vitro and substitute for it in vivo

    J. Biol. Chem

    (1994)
  • L.R. Fischer et al.

    Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man

    Exp. Neurol

    (2004)
  • S.J. Hewett et al.

    Selective potentiation of NMDA induced neuronal injury following induction of astrocytic iNOS

    Neuron

    (1994)
  • J.V. Heymach et al.

    The biosynthesis of neurotrophin heterodimers by transfected mammalian cells

    J. Biol. Chem

    (1995)
  • D. Hoyaux et al.

    S100A6, a calcium and zinc binding protein, is overexpressed in SOD1 mutant mice, a model for amyotrophic lateral sclerosis

    Biochim. Biophys. Acta

    (2000)
  • V.E. Koliatsos et al.

    Axotomy induces nerve growth factor receptor immunoreactivity in spinal motor neurons

    Brain Res

    (1991)
  • B.M. Kust et al.

    Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis

    Exp. Neurol

    (2002)
  • C.L. Lin et al.

    Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter in amyotrophic lateral sclerosis

    Neuron

    (1998)
  • A. Migheli et al.

    S 100beta protein is upregulated in astrocytes and motor neurons in the spinal cord of patients with amyotrophic lateral sclerosis

    Neurosci. Lett

    (1999)
  • H. Peluffo et al.

    Riluzole promotes survival of rat motoneurons in vitro by stimulating trophic activity produced by spinal astrocyte monolayers

    Neurosci. Lett

    (1997)
  • R. Radi et al.

    Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide

    J. Biol. Chem

    (1991)
  • C. Raoul et al.

    Active killing of neurons during development and following stress: a role for p75(NTR) and Fas?

    Curr. Opin. Neurobiol

    (2000)
  • K. Abe et al.

    Upregulation of protein tyrosine nitration in the anterior horn cells of amyotrophic lateral sclerosis

    Neurol. Res

    (1997)
  • M.E. Alexianu et al.

    Immune reactivity in a mouse model of familial ALS correlates with disease progression

    Neurology

    (2001)
  • G. Almer et al.

    Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis

    J. Neurochem

    (1999)
  • G.L. Barrett et al.

    The p75 nerve growth factor receptor mediates survival or death depending on the stage of sensory neuron development

    Proc. Natl. Acad. Sci. U. S. A

    (1994)
  • M.F. Beal et al.

    Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis

    Ann. Neurol

    (1997)
  • B. Becher et al.

    CD95–CD95L: can the brain learn from the immune system?

    Trends Neurosci

    (1998)
  • E.M. Blanc et al.

    4-hydroxynonenal, a lipid peroxidation product, impairs glutamate transport in cortical astrocytes

    Glia

    (1998)
  • J.P. Bolaños et al.

    Induction of NOS inhibits gap junction permeability in cultures rat astrocytes

    J. Neurochem

    (1996)
  • J.P. Bolaños et al.

    Effect of peroxynitrite on the mitochondrial respiratory chain: differential susceptibility of neurons and astrocytes in primary cultures

    J. Neurochem

    (1995)
  • L. Bracci-Laudiero et al.

    Multiple sclerosis patients express increased levels of nerve growth factor in cerebrospinal fluid

    Neurosci. Lett

    (1992)
  • P. Cassina et al.

    Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis

    J. Neurosci. Res

    (2002)
  • C.C. Chao et al.

    Cytokine-stimulated astrocytes damage human neurons via a nitric oxide mechanism

    Glia

    (1996)
  • A.Y. Chiu et al.

    A motor neuron-specific epitope and the low-affinity nerve growth factor receptor display reciprocal patterns of expression during development, axotomy, and regeneration

    J. Comp. Neurol

    (1993)
  • A.M. Clement et al.

    Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice

    Science

    (2003)
  • D.W. Cleveland et al.

    Oxidation versus aggregation—how do SOD1 mutants cause ALS?

    Nat. Med

    (2000)
  • D.W. Cleveland et al.

    From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS

    Nat. Rev., Neurosci

    (2001)
  • K.A. Crutcher et al.

    Detection of NGF like activity in human brain tissue: increased levels in Alzheimer's disease

    J. Neurosci

    (1993)
  • F.F. Cruz-Sanchez et al.

    Evaluation of neuronal loss, astrocytosis and abnormalities of cytoskeletal components of large motor neurons in the human anterior horn in aging

    J. Neural Transm

    (1998)
  • D.B. Drachman et al.

    Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS

    Ann. Neurol

    (2002)
  • Y. Dong et al.

    Immune function of astrocytes

    Glia

    (2001)
  • A.G. Estévez et al.

    Nitric oxide and superoxide contribute to motor neuron apoptosis induced by trophic factor deprivation

    J. Neurosci

    (1998)
  • A.G. Estévez et al.

    Induction of nitric oxide dependent apoptosis in motor neurons by zinc deficient superoxide dismutase

    Science

    (1999)
  • Cited by (264)

    • Progress in progestin-based therapies for neurological disorders

      2021, Neuroscience and Biobehavioral Reviews
    View all citing articles on Scopus
    View full text