Dietary Cholesterol and Its Effect on Tau Protein: A Study in Apolipoprotein E-Deficient and P301L Human Tau Mice

Apolipoprotein E (ApoE) is the major cholesterol transporter in the brain. There is epidemiological and experimental evidence for involvement of cholesterol metabolism in the development and progression of Alzheimer disease. A dietary effect on tau phosphorylation or aggregation, or a role of apoE in tau metabolism, has been studied experimentally, but the data are ambiguous. To elucidate the relationship between cholesterol and tau, we studied mice expressing P301L mutant human tau but not apoE (htau-ApoE(+/+)) and P301L mice with wild-type ApoE (htau-ApoE(+/+)); both genotypes develop neuron cytoskeletal changes similar to those found in Alzheimer disease. Mice were kept on a cholesterol-enriched diet or control diet for 15 weeks. The numbers of neurons with hyperphosphorylated and conformationally changed tau in the cerebral cortex were assessed by immunohistochemistry, and sterol levels were determined. Highly elevated dietary serum cholesterol levels enhanced ongoing tau pathology in htau-ApoE+/+ mice; this effect correlated with elevated brain cholesterol metabolite 27-hydroxycholesterol levels. Apolipoprotein E deficiency promoted significant increases of tau phosphorylation and conformational changes in mice on a control diet. In htau-ApoE(+/+) mice on the high cholesterol regimen, brain oxysterol levels were less than in htau-ApoE(+/+) mice, and the numbers of neurons with pathologically altered tau were similar to those in htau-ApoE(+/+) mice on the high-cholesterol diet.