NMO is an autoimmune channelopathy due to pathogenic antibodies directed against Aquaporin-4 (AQP4). Binding of NMO-IgG to astrocytic AQP4-IgG initiates complement activation, AQP4 and EAAT2 (excitatory amino acid transporter 2) down-regulation, and disruption of glutamate homeostasis resulting in primary sub-lethal and lytic astrocytic injury with secondary demyelination.
We characterized the biochemical alterations in NMO lesions using a multimodal correlative approach consisting of histopathology, Fourier Transform Infrared microscopy (FTIR) and X-Ray Fluorescent Imaging (XFI) methods. The FTIR analysis reveals overall decrease of lipids and proteins in the affected areas. In particular, the reduction of the CH2 vibration of the acyl chain of lipids (2800-3000 cm-1) as well as decrease of the lipid C=O ester peak may reflect the oxidative damage occurring in the tissue, affected by demyelinated activity. The Amide I (1600-1700 cm-1) band position and shape is sensitive to the secondary structures of proteins and oxidative damage may lead to beta aggregate formation and more disordered structures such as loops and random coils, which may appear as an additional peaks. The XFI detects the heterogeneous iron accumulation and decreased levels of sulfur and phosphorus within the lesions area. The sulfur and phosphorus decreases are well correlated with decreases of proteins and nucleic acid as seen on spectral profile of lesions. In conclusion, the loss of Myelin Associated Glycoprotein (MAG), and AQP4 corresponding to regions of low sulfur, low phosphorous, variable iron, presence of protein aggregation, oxidized lipids and cholesterol accumulation are compatible with metabolic and biochemical evidence of profound oxidative injury.