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 β-amyloid (Aβ). However, the mechanism by which cholesterol increases Aβ 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 β-amyloid precursor protein to generate Aβ, causing the accumulation of Aβ1–42 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 Aβ levels. Increased Aβ levels may in turn trigger the phosphorylation of tau by activating ERK.