Rosenthal fibers (RF), intra-astrocytic hyaline inclusions, accumulate in various pathological conditions and are the histological hallmark of
Alexander's disease. While the major
protein components of RF have been identified, the factors accounting for their pathogenesis, accumulation, and insolubility are largely unknown. In this study, we immunohistochemically examined three cases of
Alexander's disease using
antibodies to a
lysine-derived
pyrrole modification arising from
4-hydroxy-2-nonenal, a highly cytotoxic reactive
aldehyde produced by lipid peroxidation. In all the cases of
Alexander's disease examined, strong immunolabeling of RF by the
antibodies to
4-hydroxy-2-nonenal pyrrole adducts were noted. By contrast, age-matched control cases showed no immunoreactivity. These results indicate that modification of
protein by lipid peroxidation adducts may play an important role in the formation of RF as well as in the pathogenesis of
Alexander's disease. Furthermore, taken together with our previous data indicating
advanced Maillard reaction end products in RF, it seems that post-translational modification of RF, initiated by oxidative stress, is critical for both the accumulation and the insolubility of RF, and therefore, by inference, in the pathogenesis of
Alexander's disease.