Neuroinflammation in motor neuron disease

Abstract

Increasing evidence suggests that the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) is not restricted to the neurons but attributed to the abnormal interactions of neurons and surrounding glial and lymphoid cells. These findings led to the concept of non-cell autonomous neurodegeneration. Neuroinflammation, which is mediated by activated glial cells and infiltrated lymphocytes and accompanied by the subsequent production of proinflammatory cytokines and neurotoxic or neuroprotective molecules, is characteristic to the pathology in ALS and is a key component for non-cell autonomous neurodegeneration. This review covers the involvement of microglia and astrocytes in the ALS mouse models and human ALS, and it also covers the deregulated pathways in motor neurons, which are involved in initiating the disease. Based on the cell-type specific pathomechanisms of motor neuron disease, targeting of neuroinflammation could lead to future therapeutic strategies for ALS and could be potentially applied to other neurodegenerative diseases.

Keywords: ALS; glia; neurodegenerative disease; neuroinflammation.

Fig. 1

Activated microglia and astrocytes in the lumbar spinal cord of mutant SOD1 mice. Lumbar spinal cord sections from SOD1^G93A mice at pre-onset (A), symptomatic stage (B), and end-stage (C) were stained with antibodies for ChAT (cholinergic motor neuron, blue), GFAP (astrocytes, green), and Iba-1 (microglia, red). Anterior horn regions were shown. Prominent activation of microglia and astrocytes with motor neuron loss were observed (B and C). Scale bar: 100μm.

Fig. 2

Cell and non-cell autonomous neurodegeneration in ALS. Age-dependent accumulation of damage within motor neurons initiates motor neuron disease. Unidentified factors derived from damaged motor neurons cause microglial activation. Astrocytes and infiltrated T lymphocytes also regulate activation status of microglia. Abnormally activated microglia and astrocytes produce high levels of proinflammatory molecules, together with losses of neuroprotective properties from those glial cells, cause further damage to motor neurons, hence, driving rapid disease progression. Among the numerous factors secreted from diseased astrocytes, we identified TGF-β1 as one of the exacerbation factors to drive disease progression through interfering the neuroprotective reaction mediated by microglia and T lymphocytes.