Hypercholesterolemia-induced Abeta accumulation in rabbit brain is associated with alteration in IGF-1 signaling

Hypercholesterolemia increases levels of beta-amyloid (Abeta), a peptide that accumulates in Alzheimer's disease brains. Because cholesterol in the blood does not cross the blood brain barrier (BBB), the link between circulating cholesterol and Abeta accumulation is not understood. In contrast to cholesterol, the oxidized cholesterol metabolite 27-hydroxycholesterol can cross the BBB, potentially increasing Abeta levels. However, the mechanisms by which cholesterol or 27-hydroxycholesterol regulate Abeta levels are not known. The insulin-like growth factor-1 (IGF-1) regulates the glycogen-synthase kinase-3alpha (GSK-3alpha) and the insulin degrading enzyme (IDE). While GSK-3alpha increases Abeta production, IDE is a major Abeta-degrading enzyme. We report here that feeding rabbits with a cholesterol-enriched diet increases Abeta levels in the hippocampus, an effect that is associated with reduced IGF-1 levels. 27-hydroxycholesterol also increases Abeta and reduces IGF-1 levels in organotypic hippocampal slices from adult rabbits. We suggest that hypercholesterolemia-induced Abeta accumulation may be mediated by 27-hydroxycholesterol, involving IGF-1 signaling.