Although dyslipidemia and lipid accumulation are established risk factors for numerous neurological diseases, including stroke and neurodegenerative disorders, whether dyslipidemia directly causes neuronal death or acts as a secondary factor remains debatable. To answer this question, ApoE-knockout is a more suitable model than ApoE4 mutants to study dyslipidemia because the E4 allele manifests an isoform-specific structural conformation that produces allele-specific effects. In this study, we examined neurological phenotype and mitochondrial and metabolic alterations in ApoE-knockout mice, which exhibited elevated serum cholesterol and triglyceride levels from an early age. These mutant mice exhibited mild cognitive phenotypes, suggesting that the functions of the cerebral cortex were affected by lipid dysregulation. Decreased electron transport chain complex IV activity indicated compromised mitochondrial function in 1-year-old mutant mice. Increased oxidative stress in cortical tissues, and downregulated expression of the key antioxidative genes indicated increased oxidative stress and mitochondrial damage in the mutant mice. Decreased mitochondrial mass was also observed, possibly due to the increase of mitophagy. However, no extensive cell death or significant reduction in cortical neuronal count was detected although the neurites degenerated in 1-year-old mutant mice. Upregulation of the Pgc1a gene, a master regulator of mitochondrial biogenesis, suggested the presence of protective mechanisms in the brain. Collectively, these findings, together with the phenotypes developed in Ldlr-/- mutant mice, suggest that hyperlipidemia alone may be insufficient to induce significant neurodegeneration. There should be additional factors that play a crucial role in the pathogenesis of these diseases.
