title: High cholesterol content in neurons increases BACE, beta-amyloid, and phosphorylated tau levels in rabbit hippocampus.
abstract: 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.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, 58202, USA. oghribi@medicine.nodak.edu
authors.forename: Othman
authors.initials: O
authors.lastname: Ghribi
authors.forename: Brian
authors.initials: B
authors.lastname: Larsen
authors.forename: Matthew
authors.initials: M
authors.lastname: Schrag
authors.forename: Mary M
authors.initials: MM
authors.lastname: Herman
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D010450:Endopeptidases / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047468:Immunoprecipitation / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D011897:Random Allocation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002791:Cholesterol, Dietary; D009419:Nerve Tissue Proteins; D016875:tau Proteins; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases