Alexander Disease: Alzheimer Disease of the Developing Brain?

Alexander disease is a leukodystrophy-like neurodegenerative disease that typically presents in infancy or childhood. The disease is essentially a sporadic condition, and there is no known genetic predisposition or metabolic abnormality. The hallmark of the disease is the diffuse accumulation of Rosenthal fibers (RF) throughout the central nervous system. Although an etiological relationship of the RF to disease pathogenesis has been suspected since the initial description of Alexander disease, such a relationship has not been confirmed. We previously identified a number of oxidative post-translational modifications, including advanced glycation end products and lipid peroxidation adducts, in intimate association with the RF of Alexander disease. Such oxidative protein damage provides a mechanism, through protein crosslinking, for insolubility and accumulation of RF. Notably, these findings show a striking parallel with the biochemical features of age-related neurodegenerative diseases such as Alzheimer disease. Therefore, Alexander disease and Alzheimer disease likely share a common pathogenesis, namely oxidative injury as a potential primary process in the etiology and pathogenesis.