A high-fat diet disrupts neural tracts in apolipoprotein E mouse models

Diet-induced obesity is becoming increasingly prevalent, and its impact on brain pathology is gaining recognition. Apolipoprotein E (ApoE), a key regulator of lipid transport, exhibits isoform-specific differences in its relationship with brain disorders. This study examined how high-fat diet (HFD)-induced obesity affects brain function and structure across ApoE isoforms. Male knock-in (ApoE3, ApoE4) and knockout (KO) mice were fed an HFD for 6 months starting at 3 months of age. All genotypes experienced weight gain and elevated blood glucose levels. Diffusion tensor imaging (DTI) revealed reduced fractional anisotropy (FA) in the corpus callosum of all HFD-fed mice, with an additional FA reduction in the cingulum of ApoE3 mice. Immunohistochemical analysis of the corpus callosum showed diminished remyelinating oligodendrocytes in KO mice compared to their regular-diet counterparts and ApoE3 mice. In the cortex, Western blotting revealed a diet-specific trend toward reduced axonal skeletal proteins (β3-tubulin) in ApoE3 mice, leading to a significant difference between ApoE3 and ApoE4 mice on HFD. Conversely, lower levels of myelin basic protein (MBP) in ApoE3 mice compared to ApoE4 mice at baseline became negligible when HFD was introduced, due to an overall increase in MBP levels in ApoE3 mice. These findings indicate that neural tracts are the primary brain substrate affected by HFD-induced obesity in human ApoE mouse models, with more pronounced effects in ApoE3 and KO mice than in ApoE4 mice. Specifically, ApoE3 mice exhibited axon skeletal damage, while KO mice showed impaired remyelination.