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Paradoxical effects of apolipoprotein E on cognitive function and clinical progression in mice with experimental autoimmune encephalomyelitis

Dayger, CA;Rosenberg, JS;Winkler, C;Foster, S;Witkowski, E;Benice, TS;Sherman, LS;Raber, J;

Multiple sclerosis (MS) is an inflammatory demyelinating disease characterized by sensory, motor, and cognitive impairments. Apolipoprotein E (apoE) plays an important role in cholesterol and lipid metabolism in the brain and in susceptibility to cognitive impairment and pathology following brain injury. Studies in mice with a mild form of experimental autoimmune encephalomyelitis (EAE), an MS animal model, support only protective roles for apoE in MS. We examined behavioral and cognitive changes prior to onset of clinical disease and the onset and progression of a more severe form of EAE in female Apoe(-/-) and C57Bl/6 wild-type mice. Apoe(-/-) mice had a later day of onset, a later day of peak symptoms and disease severity, and a lower cumulative disease index compared to wild type mice. Apoe(-/-) mice also showed decreased CD4+ cell invasion following EAE induction compared to wild type mice, and less spinal cord demyelination at 17 but not 30 days following EAE induction. In contrast, EAE-challenged Apoe(-/-) mice showed reduced exploratory activity, rotorod performance, and impaired contextual fear conditioning compared to wild type animals. These data indicate paradoxical effects of apoE on EAE-induced behavioral and cognitive changes and the onset and progression of clinical disease.