Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological disorder characterized by early autonomic dysfunction, cognitive impairment, pyramidal tract and cerebellar dysfunction, and white matter loss in the central nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression.
This transgenic model of ADLD expresses four times the normal levels of full-length mouse Lmnb1 under the control of the endogenous promoter and regulatory sequences. Expression levels are approximately 4-fold higher compared with wildtype.
Animals are born healthy and are overtly indistinguishable from control littermates, but eventually recapitulate many of the features of ADLD. Mice exhibit cognitive impairment and epilepsy, followed by age-dependent motor deficits.
Substantial spatial memory deficits are observed at 12 months of age in a Morris water maze assay and exhibit impairments in a step-through passive avoidance task, which reflects long-term spatial associative learning and fear memory of an aversive experience. Transgenic animals exhibit progressive motor impairment on 2 different motor tasks, the accelerated rotarod (at 24 months of age) and balance beam (progressing at 12 months).
Frequent behavioral seizures, varying from generalized spasms and tremors to generalized clonic activity with atonia and tail extension are seen. Cortical EEG reveals frequent spontaneous epileptic activity, including epileptiform discharges and seizures. Transgenic mice exhibit an approximately 20-fold increase in the number of interictal spikes. Overexpression results in aberrant myelin formation and axonal degeneration (at 12 months of age), and demyelination (by 24 months).
