Affiliations: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
Correspondence:
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Correspondence to: Othman Ghribi, Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, North Dakota, 58202, USA. Tel.: +1 701 777 2522; Fax: +1 701 777 4490; E-mail: oghribi@medicine.nodak.edu.
Abstract: Accumulation of amyloid-β (Aβ) 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 Aβ and phosphorylated tau levels. However, the mechanisms by which cholesterol and 27-OHC regulate Aβ production and tau phosphorylation remain unclear. Leptin, an adipocytokine involved in cell survival and in learning, has been demonstrated to regulate Aβ production and tau hyperphosphorylation in transgenic mice for AD. However, the involvement of leptin signaling in cholesterol and cholesterol metabolites-induced Aβ 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 ∼80% and incubating organotypic slices from adult rabbit hippocampus with 27-OHC reduced leptin levels by ∼30%. 27-OHC induces a 1.5-fold increase in Aβ40 and a 3-fold increase in Aβ42 and in phosphorylated tau. Treatment with leptin reversed the 27-OHC-induced increase in Aβ and phosphorylated tau by decreasing the levels of BACE-1 and GSK-3β 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.
Keywords: BACE-1, cholesterol, GSK-3β, hippocampus, 27-hydroxycholesterol, leptin, organotypic slices, tau
