High cholesterol content in neurons increases BACE, beta-amyloid, and phosphorylated tau levels in rabbit hippocampus.

Epidemiological, cellular, and animal studies suggest that abnormalities in cholesterol metabolism may contribute to the etiology of Alzheimer's disease by increasing the generation of beta-amyloid (Abeta). However, the mechanism by which cholesterol increases Abeta levels is not fully understood. In the present study, we demonstrate that feeding rabbits with 1% cholesterol for 7 months causes an increase in cholesterol content in neurons. High cholesterol content in neurons is accompanied by an increase in the level of BACE1, the enzyme that initially cleaves beta-amyloid precursor protein to generate Abeta, causing the accumulation of Abeta1-42 peptide. These effects correlate with the phosphorylation of tau and the activation of extracellular signal-regulated protein kinase (ERK). Our data suggest that excessive cholesterol content in neurons, following long-term dietary cholesterol, may underlie the increase in BACE1 and Abeta levels. Increased Abeta levels may in turn trigger the phosphorylation of tau by activating ERK.