Caffeine protects against oxidative stress and Alzheimer's disease-like pathology in rabbit hippocampus induced by cholesterol-enriched diet

Cholesterol has been linked to the pathogenesis of sporadic Alzheimer's disease (AD) as a risk factor increasing [beta-amyloid (A beta) and oxidative stress levels. Caffeine has antioxidant properties and has been demonstrated to reduce A beta levels in transgenic mouse models of familial AD. However, the effects of caffeine on cholesterol-induced sporadic AD pathology have not been determined. In this study, we determined the effects of caffeine on A beta levels, tau phosphorylation, oxidative stress generation, and caffeine-target receptors in rabbits fed a 2% cholesterol-enriched diet, a model system for sporadic AD. Our results showed that the cholesterol-enriched diet increased levels of A beta, tau phosphorylation, and oxidative stress measured as increased levels of reactive oxygen species and isoprostanes, glutathione depletion, and increased levels of endoplasmic reticulum stress marker proteins. Additionally, the cholesterol-enriched diet reduced the levels of adenosine A(1) receptors (A(1)R) but not ryanodine or adenosine A(2A) receptors. Caffeine, administered at 0.5 and 30 mg/day in the drinking water, reduced the cholesterol-induced increase in A beta, phosphorylated tau, and oxidative stress levels and reversed the cholesterol-induced decrease in AIR levels. Our results suggest that even very low doses of caffeine might protect against sporadic AD-like pathology. (C) 2010 Elsevier Inc. All rights reserved.