Cholesterol causes Alzheimer pathology through Akt/mTOR inhibition

Abstract

Alzheimer's disease (AD) is a complex disorder for which there is currently no medicine that can prevent its progression. The causes of AD are not yet completely understood but genetic, environmental, and dietary factors may contribute to the pathogenesis of this devastating disorder. Epidemiological, genome-wide association, postmortem, animal, and cellular studies strongly suggest that high plasma cholesterol is a risk factor for AD. However, the mechanisms by which cholesterol may cause AD are ill-defined. We tested the hypothesis that cholesterol-enriched diets cause AD hallmarks by mechanisms involving the down-regulation of the Akt/mTOR pathway. New Zealand white male rabbits (4 ± 0.4 kg and 3 ± 0.25 year old) were used in this study. Animals were randomly assigned to 2 groups as follows: Group 1 (n = 6), normal chow and group 2 (n = 6), chow supplemented with 2% cholesterol . Cholesterol-treated animals and their matched controls were euthanized 12 weeks later. Cholesterol-enrichded diets inhibit active Akt and m-TOR. Inhibition of Akt is associated with increased levels of GSK3αβ, an enzyme that increases β-amyloid and phosphorylated tau production. Inhibition of mTOR also causes tau hyperphosphorylation. Our results suggest that cholesterol-enriched diets cause AD-like pathology by mechanisms involving an Akt/mTOR signaling pathway.