DEMYELINATION IN A TRANSGENIC MOUSE - A MODEL FOR MULTIPLE-SCLEROSIS

A transgenic mouse containing 70 copies (ND4) of the transgene encodin g DM20, a myelin proteolipid protein, appeared clinically normal up to 3 months of age. By 8-10 months, it showed tremors, unsteady gait, an d died shortly thereafter. We concluded that the clinical symptoms cor related with demyelination based on the following criteria: 1) at 10 m onths of age only 17% of the amount of myelin obtained from normal mic e was isolated from the ND4 mice; 2) astrogliosis, a prominent feature of demyelinating disease was minimal at 3 months of age but prominent by 10 months; 3) at the electron microscopic level disrupted myelin w as seen at 8 months of age in the ND4 mice and ingested myelin debris was found in astrocytes; 4) lymphocytic infiltration in association wi th endothelial cells was observed routinely in the ND4 mice; 5) sectio ns through optic nerves showed denuded and thinly myelinated axons in the 8 month old ND4 mice. Although the mechanism by which demyelinatio n takes place is not fully understood, measurements of the amounts of PLP suggest it is down-regulated by the large amount of DM20. Since DM 20 is a major proteolipid in the young but a minor one in the adult, t he persistence of high levels in the adult results in improperly assem bled myelin which is prone to disruption. Therefore demyelination in t he ND4 mouse appears to result from the persistence of immature myelin into the adult. (C) 1993 Wiley-Liss, Inc.