Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus–Merzbacher disease
Stumpf, Sina K. ; Berghoff, Stefan A. ; Trevisiol, Andrea ; Spieth, Lena ; Düking, Tim ; Schneider, Lennart V. ; Schlaphoff, Lennart ; Dreha-Kulaczewski, Steffi et al.
Citable Link (URL):http://resolver.sub.uni-goettingen.de/purl?gs-1/16260
Pelizaeus-Merzbacher disease (PMD) is an untreatable and fatal leukodystrophy. In a model of PMD with perturbed blood-brain barrier integrity, cholesterol supplementation promotes myelin membrane growth. Here, we show that in contrast to the mouse model, dietary cholesterol in two PMD patients did not lead to a major advancement of hypomyelination, potentially because the intact blood-brain barrier precludes its entry into the CNS. We therefore turned to a PMD mouse model with preserved blood-brain barrier integrity and show that a high-fat/low-carbohydrate ketogenic diet restored oligodendrocyte integrity and increased CNS myelination. This dietary intervention also ameliorated axonal degeneration and normalized motor functions. Moreover, in a paradigm of adult remyelination, ketogenic diet facilitated repair and attenuated axon damage. We suggest that a therapy with lipids such as ketone bodies, that readily enter the brain, can circumvent the requirement of a disrupted blood-brain barrier in the treatment of myelin disease.