High cholesterol content in neurons increases BACE, β-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 (A beta). However, the mechanism by which cholesterol increases A beta 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 BACE 1, the enzyme that initially cleaves beta-amyloid precursor protein to generate A, causing the accumulation of A beta 1 -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 A beta levels. Increased A beta levels may in turn trigger the phosphorylation of tau by activating ERK. (c) 2006 Elsevier Inc. All rights reserved.