In Vivo Imaging Reveals Rapid Astrocyte Depletion and Axon Damage in a Modelof Neuromyelitis Optica-Related Pathology
Objective: Neuromyelitis optica (NMO) is an autoimmune disease of the central nervous system, which resemblesmultiple sclerosis (MS). NMO differs from MS, however, in the distribution and histology of neuroinflammatorylesions and shows a more aggressive clinical course. Moreover, the majority of NMO patients carry immunoglobulinG autoantibodies against aquaporin-4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damageastrocytes by 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 themechanisms 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 power-ful 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 2 hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astro-cyte toxicity and axon damage were dependent on AQP4 antibody titer and complement, specifically C1q.Interpretation: In vivo imaging of the spinal cord reveals the swift development of NMO-related acute axon injuryafter AQP4 antibody-mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlyingthe spread of NMO pathology beyond astrocytes, as well as in evaluating potential neuroprotective interventions.
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