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Paradoxical effects of apolipoprotein E on cognitive function and clinical progression in mice with experimental
Catherine A Dayger1, Jenna S Rosenberg, Clayton Winkler
1Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
Abstract:
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.
Insights
Apolipoprotein E deficiency paradoxically impacts experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. ApoE knockout mice showed delayed disease onset but worsened cognitive and motor deficits, suggesting complex roles in neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Multiple sclerosis (MS) is an inflammatory demyelinating disease impacting neurological function.
- Apolipoprotein E (apoE) influences brain lipid metabolism and cognitive function.
- Previous studies suggested protective roles for apoE in milder MS models.
Purpose of the Study:
- To investigate the role of apoE in a severe mouse model of experimental autoimmune encephalomyelitis (EAE).
- To examine behavioral and cognitive changes in apoE-deficient mice during EAE progression.
Main Methods:
- Comparison of EAE onset, severity, and progression in apoE knockout (Apoe(-/-)) and wild-type (C57Bl/6) female mice.
- Assessment of immune cell infiltration (CD4+ cells) and spinal cord demyelination.
- Evaluation of behavioral and cognitive functions including exploratory activity, rotorod performance, and fear conditioning.
Main Results:
- Apoe(-/-) mice exhibited delayed EAE onset, peak symptoms, and reduced overall disease severity.
- Reduced CD4+ T cell invasion and less spinal cord demyelination were observed in Apoe(-/-) mice at early stages.
- Despite milder clinical disease, Apoe(-/-) mice displayed significant deficits in exploratory activity, motor coordination, and contextual fear conditioning.
Conclusions:
- Apolipoprotein E plays paradoxical roles in the EAE model of multiple sclerosis.
- While apoE deficiency may delay disease onset and reduce inflammation, it exacerbates behavioral and cognitive impairments.
- These findings highlight the complex involvement of apoE in neuroinflammation and neurological deficits relevant to MS.
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