Journal of Neuroimmune Pharmacology

, Volume 4, Issue 4, pp 389–398 | Cite as

Microglia in ALS: The Good, The Bad, and The Resting

  • Jenny S. Henkel
  • David R. Beers
  • Weihua Zhao
  • Stanley H. Appel
Invited Review

Abstract

Inflammation, including microglial activation and T cell infiltration, is a neuropathological hallmark of amyotrophic lateral sclerosis (ALS), a rapidly progressing neurodegenerative disease. The identification of mutations in the gene for Cu2+/Zn2+ superoxide dismutase (SOD1) from patients with an inherited form of ALS enabled the creation of transgenic mice overexpressing mutant forms of SOD1 (mSOD1) which develop a motoneuron disease that resembles the disease seen in ALS patients. These transgenic mice display similar inflammatory reactions at sites of motoneuron injury as detected in ALS patients, enabling the observation that this inflammation is not simply a late consequence of motoneuron degeneration, but actively contributes to the balance between neuroprotection and neurotoxicity. The microglial and T cell activation states influence the rate of disease progression. Initially, microglia and T cells can slow disease progression, while they may later contribute to the acceleration of disease. Accumulation of intracellular and extracellular misfolded mSOD1 may be key events regulating the transformation from neuroprotective alternatively activated M2 microglia to cytotoxic classically activated M1 microglia. Intracellular and extracellular mSOD1 utilizing different pathways may enhance the production and release of reactive oxygen species (ROS) and augment the inflammatory cytokine cascade from microglia. These ROS and cytokines may increase the susceptibility of motoneurons to glutamate toxicity and inhibit the function and expression of astrocytic glutamate transporters resulting in further neurotoxicity. Thus, the cumulative evidence suggests that inflammation plays a central role in ALS and manipulating these microglial effector functions may potentially modify the outcome of this devastating disease.

Keywords

M2 alternatively activated M1 classically activated regulatory Treg 

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jenny S. Henkel
    • 1
  • David R. Beers
    • 1
  • Weihua Zhao
    • 1
  • Stanley H. Appel
    • 1
  1. 1.Department of Neurology, Methodist Neurological Institute, The Methodist Hospital Research InstituteThe Methodist HospitalHoustonUSA

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