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Neuroprotective effects of toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration.

ABSTRACT: Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we characterized both the proinflammatory and neurotoxic effects of TLR4 activation with lipopolysaccharide (activation of microglial cells, release of proinflammatory cytokines and motor neuron death) and the protective effects of a cyanobacteria-derived TLR4 antagonist (VB3323). With the use of TLR4-deficient cells, a critical role of the microglial component with functionally active TLR4 emerged in this setting. The in vivo experiments were carried out in a mouse model of spontaneous motor neuron degeneration, the wobbler mouse, where we preliminarily confirmed a protective effect of TLR4 antagonism. Compared with vehicle- and riluzole-treated mice, those chronically treated with VB3323 showed a decrease in microglial activation and morphological alterations of spinal cord neurons and a better performance in the paw abnormality and grip-strength tests. Taken together, our data add new understanding of the role of TLR4 in mediating neurotoxicity in the spinal cord and suggest that TLR4 antagonists could be considered in future studies as candidate protective agents for motor neurons in degenerative diseases.

SUBMITTER: De Paola M

PROVIDER: S-EPMC3459480 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Neuroprotective effects of toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration.

De Paola Massimiliano M Mariani Alessandro A Bigini Paolo P Peviani Marco M Ferrara Giovanni G Molteni Monica M Gemma Sabrina S Veglianese Pietro P Castellaneta Valeria V Boldrin Valentina V Rossetti Carlo C Chiabrando Chiara C Forloni Gianluigi G Mennini Tiziana T Fanelli Roberto R

Molecular medicine (Cambridge, Mass.) 20120907

Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we ch ...[more]

PMID: 22562723

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Project description:Neurodegenerative diseases are characterized by the selective degeneration of neuronal populations in different brain regions and frequently the formation of distinct protein aggregates that often overlap between diseases. While the causes of many sporadic neurodegenerative diseases are unclear, genes associated with familial or sporadic forms of disease and the underlying cellular pathways involved tend to support common disease mechanisms. Underscoring this concept, mutations in the Vacuolar Protein Sorting 35 Orthologue (VPS35) gene have been identified to cause late-onset, autosomal dominant familial Parkinson's disease, whereas reduced VPS35 protein levels are reported in vulnerable brain regions of subjects with Alzheimer's disease, neurodegenerative tauopathies such as progressive supranuclear palsy and Pick's disease, and amyotrophic lateral sclerosis. Therefore, VPS35 is commonly implicated in many neurodegenerative diseases. VPS35 plays a critical role in the retromer complex that mediates the retrieval and recycling of transmembrane protein cargo from endosomes to the trans-Golgi network or plasma membrane. VPS35 and retromer function are highly conserved in eukaryotic cells, with the homozygous deletion of VPS35 inducing early embryonic lethality in mice that has hindered an understanding of its role in the brain. Here, we develop conditional knockout mice with the selective deletion of VPS35 in neurons to better elucidate its role in neuronal viability and its connection to neurodegenerative diseases. Surprisingly, the pan-neuronal deletion of VPS35 induces a progressive and rapid disease with motor deficits and early post-natal lethality. Underlying this neurological phenotype is the relatively selective and robust degeneration of motor neurons in the spinal cord. Neuronal loss is accompanied and preceded by the formation of p62-positive protein inclusions and robust reactive astrogliosis. Our study reveals a critical yet unappreciated role for VPS35 function in the normal maintenance and survival of motor neurons during post-natal development that has important implications for neurodegenerative diseases, particularly amyotrophic lateral sclerosis.

Dataset Information

Neuroprotective effects of toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration.

Publications

Neuroprotective effects of toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration.

Similar Datasets

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