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In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology

Ann Neurol. 2016 Mar 6. doi: 10.1002/ana.24630. [Epub ahead of print]

Authors/Editors: Herwerth M, Kalluri SR, Srivastava R, Kleele T, Kenet S, Illes Z, Merkler D, Bennett JL, Misgeld T, Hemmer B.
Publication Date: 2016

2016_03_herwerth

Abstract

OBJECTIVE:
Neuromyelitis optica (NMO) is an autoimmune disease of the CNS, which resembles multiple sclerosis (MS). NMO differs from MS, however, in the distribution and histology of neuroinflammatory lesions and shows a more aggressive clinical course. Moreover, the majority of NMO patients carry IgG autoantibodies against aquaporin-4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damage astrocytes via complement, but NMO histopathology also shows demyelination, and – importantly – axon injury, which may determine permanent deficits following NMO relapses. The dynamics of astrocyte injury in NMO and the mechanisms by which toxicity spreads to axons are not understood.

METHODS:
Here, we establish in vivo imaging of the spinal cord, one of the main sites of NMO pathology, as a powerful tool to study the formation of experimental NMO-related lesions caused by human AQP4 antibodies in mice.

RESULTS:
We found that human AQP4 antibodies caused acute astrocyte depletion with initial oligodendrocyte survival. Within two hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astrocyte toxicity and axon damage were dependent on AQP4 antibody concentration and complement, specifically C1q.

INTERPRETATION:
In vivo imaging of the spinal cord reveals the swift development of NMO-related acute axon injury following AQP4 antibody-mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlying the spread of NMO pathology beyond astrocytes, as well as in evaluating potential neuroprotective interventions.

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