Leptin Reduces the Accumulation of A beta and Phosphorylated Tau Induced by 27-Hydroxycholesterol in Rabbit Organotypic Slices

Accumulation of amyloid-beta (A beta) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer's disease (AD). We have shown that cholesterol-enriched diets and its metabolite 27-hydroxycholesterol (27-OHC) increase A beta and phosphorylated tau levels. However, the mechanisms by which cholesterol and 27-OHC regulate A beta production and tau phosphorylation remain unclear. Leptin, an adipocytokine involved in cell survival and in learning, has been demonstrated to regulate A beta production and tau hyperphosphorylation in transgenic mice for AD. However, the involvement of leptin signaling in cholesterol and cholesterol metabolites-induced A beta accumulation and tau hyperphosphorylation are yet to be examined. In this study, we determined the effect of high cholesterol diet and 27-OHC on leptin expression levels and the extent to which leptin treatment affects 27-OHC-induced AD-like pathology. Our results show that feeding rabbits a 2% cholesterol-enriched diet for 12 weeks reduces the levels of leptin by similar to 80% and incubating organotypic slices from adult rabbit hippocampus with 27-OHC reduced leptin levels by similar to 30%. 27-OHC induces a 1.5-fold increase in A beta(40) and a 3-fold increase in A beta(42) and in phosphorylated tau. Treatment with leptin reversed the 27-OHC-induced increase in A beta and phosphorylated tau by decreasing the levels of BACE-1 and GSK-3 beta respectively. Our results suggest that cholesterol-enriched diets and cholesterol metabolites induce AD-like pathology by altering leptin signaling. We propose that leptin administration may prevent the progression of sporadic forms of AD that are related to increased cholesterol and oxidized cholesterol metabolite levels.