Limits...
Neuroinflammation in motor neuron disease.

Komine O, Yamanaka K - Nagoya J Med Sci (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4664586&req=5

fig2: 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.

Mentions: Gliosis has long been known as a component of ALS pathology, with microgliosis being recognized in the past 20 years.24) Research using positron emission tomography provided direct evidence of microglial activation in the brains of living patients with ALS. The intensity of microglial activation was correlated with the severity of disease, suggesting active involvement of microglial activation in ALS.25) Microgliosis and inflammation have been demonstrated multiple times in lesions of mutant SOD1 mice and human with ALS. These lesions contain elevated levels of proinflammatory molecules such as cytokines (TNF-α: tumor necrosis factor-α, IL-1β: interleukin-1β, IL-12: interleukin-12, IFN-γ: interferon-γ, and others), reactive oxygen species (superoxide, nitric oxide, and its derivatives), chemokines, and glutamate.26-29) Microglia also produce mitogenic factors (macrophage colony stimulating factor), anti-inflammatory cytokines (TGF-β: transforming growth factor-β), and neurotrophic factors (IGF-1: insulin-like growth factor-1), suggesting that there is a neuroprotective component in neuroinflammation (Figure 2).


Neuroinflammation in motor neuron disease.

Komine O, Yamanaka K - Nagoya J Med Sci (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664586&req=5

fig2: 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.
Mentions: Gliosis has long been known as a component of ALS pathology, with microgliosis being recognized in the past 20 years.24) Research using positron emission tomography provided direct evidence of microglial activation in the brains of living patients with ALS. The intensity of microglial activation was correlated with the severity of disease, suggesting active involvement of microglial activation in ALS.25) Microgliosis and inflammation have been demonstrated multiple times in lesions of mutant SOD1 mice and human with ALS. These lesions contain elevated levels of proinflammatory molecules such as cytokines (TNF-α: tumor necrosis factor-α, IL-1β: interleukin-1β, IL-12: interleukin-12, IFN-γ: interferon-γ, and others), reactive oxygen species (superoxide, nitric oxide, and its derivatives), chemokines, and glutamate.26-29) Microglia also produce mitogenic factors (macrophage colony stimulating factor), anti-inflammatory cytokines (TGF-β: transforming growth factor-β), and neurotrophic factors (IGF-1: insulin-like growth factor-1), suggesting that there is a neuroprotective component in neuroinflammation (Figure 2).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

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.

No MeSH data available.


Related in: MedlinePlus