Aquaporin-4 Expression during Toxic and Autoimmune Demyelination.

Sven Olaf Rohr,Markus Kipp,Sarah Joost,Paul Van Der Valk,Sandra Amor,Christoph Schmitz,Theresa Greiner

doi:10.3390/cells9102187

Abstract

The water channel protein aquaporin-4 (AQP4) is required for a normal rate of water exchange across the blood–brain interface. Following the discovery that AQP4 is a possible autoantigen in neuromyelitis optica, the function of AQP4 in health and disease has become a research focus. While several studies have addressed the expression and function of AQP4 during inflammatory demyelination, relatively little is known about its expression during non-autoimmune-mediated myelin damage. In this study, we used the toxin-induced demyelination model cuprizone as well as a combination of metabolic and autoimmune myelin injury (i.e., Cup/EAE) to investigate AQP4 pathology. We show that during toxin-induced demyelination, diffuse AQP4 expression increases, while polarized AQP4 expression at the astrocyte endfeet decreases. The diffuse increased expression of AQP4 was verified in chronic-active multiple sclerosis lesions. Around inflammatory brain lesions, AQP4 expression dramatically decreased, especially at sites where peripheral immune cells penetrate the brain parenchyma. Humoral immune responses appear not to be involved in this process since no anti-AQP4 antibodies were detected in the serum of the experimental mice. We provide strong evidence that the diffuse increase in anti-AQP4 staining intensity is due to a metabolic injury to the brain, whereas the focal, perivascular loss of anti-AQP4 immunoreactivity is mediated by peripheral immune cells.

Highlights

Multiple sclerosis (MS) is widely considered to be an autoimmune, demyelinating disease of the central nervous system (CNS)
We performed immunohistochemical stains to investigate AQP4 expression and determined whether expression levels are higher in regions that show predominant demyelination in the cuprizone-model
Determined whether expression levels are higher in regions that show predominant demyelination in the cuprizone-model

Summary

Introduction

Multiple sclerosis (MS) is widely considered to be an autoimmune, demyelinating disease of the central nervous system (CNS). Histopathological characteristics are demyelination, peripheral immune cell infiltration, gliosis, and axonal damage [1,2], which creates a neurodegenerative environment that leads to the accumulation of significant motor, sensory, and cognitive disabilities. It is widely assumed that adaptive immunity generates lesions following the entry of leucocytes into the CNS [3]. These are associated with blood–brain barrier dysfunction, oligodendrocyte death, and the generation of demyelinated lesions within the white and grey matter. During the last decades, the autoimmune aspects of the MS pathology have been in the focus of research efforts, in particular

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