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

Abstract Hypercholesterolemia increases levels of β-amyloid (Aβ), 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 Aβ accumulation is not understood. In contrast to cholesterol, the oxidized cholesterol metabolite 27-hydroxycholesterol can cross the BBB, potentially increasing Aβ levels. However, the mechanisms by which cholesterol or 27-hydroxycholesterol regulate Aβ levels are not known. The insulin-like growth factor-1 (IGF-1) regulates the glycogen-synthase kinase-3α (GSK-3α) and the insulin degrading enzyme (IDE). While GSK-3α increases Aβ production, IDE is a major Aβ-degrading enzyme. We report here that feeding rabbits with a cholesterol-enriched diet increases Aβ levels in the hippocampus, an effect that is associated with reduced IGF-1 levels. 27-hydroxycholesterol also increases Aβ and reduces IGF-1 levels in organotypic hippocampal slices from adult rabbits. We suggest that hypercholesterolemia-induced Aβ accumulation may be mediated by 27-hydroxycholesterol, involving IGF-1 signaling.