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Neurotherapeutics. 2015 Apr;12(2):364-75. doi: 10.1007/s13311-014-0329-3.

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis.

Author information

1
Department of Neurology, Houston Methodist Neurological Institute, Peggy and Gary Edwards ALS Research Laboratory, Houston Methodist Hospital Research Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.

Abstract

Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by loss of motor neurons, resulting in paralysis and death. Multiple mechanisms of motor neuron injury have been implicated based upon the more than 20 different genetic causes of familial ALS. These inherited mutations compromise diverse motor neuron pathways leading to cell-autonomous injury. In the ALS transgenic mouse models, however, motor neurons do not die alone. Cell death is noncell-autonomous dependent upon a well orchestrated dialogue between motor neurons and surrounding glia and adaptive immune cells. The pathogenesis of ALS consists of 2 stages: an early neuroprotective stage and a later neurotoxic stage. During early phases of disease progression, the immune system is protective with glia and T cells, especially M2 macrophages/microglia, and T helper 2 cells and regulatory T cells, providing anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a second rapidly progressing phase develops, characterized by M1 macrophages/microglia, and proinflammatory T cells. In rapidly progressing ALS patients, as in transgenic mice, neuroprotective regulatory T cells are significantly decreased and neurotoxicity predominates. Our own therapeutic efforts are focused on modulating these neuroinflammatory pathways. This review will focus on the cellular players involved in neuroinflammation in ALS and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity with the goal of arresting the progressive and devastating nature of ALS.

PMID:
25567201
PMCID:
PMC4404435
DOI:
10.1007/s13311-014-0329-3
[Indexed for MEDLINE]
Free PMC Article

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