Regulation of beta-amyloid levels in the brain of cholesterol-fed rabbit, a model system for sporadic Alzheimer's disease.
Accumulation of beta-amyloid (Abeta) peptide in the brain is a major hallmark of Alzheimer's disease (AD). Hypercholesterolemia is a risk factor for AD and has been shown by laboratory studies to cause Abeta accumulation. Abeta levels in the brain are governed by its generation from amyloid precursor protein by beta-secretase (BACE1), degradation by the insulin degrading enzyme (IDE), clearance from the brain by the low density lipoprotein receptor-related protein (LRP-1), and transport from circulation into the brain by receptor for advanced glycation end products (RAGE). However, the mechanisms by which hypercholesterolemia causes Abeta accumulation in the brain and contributes to the pathogenesis of AD are still to be determined. In the present study, we determined the extent to which hypercholesterolemia-induced Abeta accumulation is associated with alterations in BACE1, IDE, LRP-1, and RAGE expression levels. We show that hypercholesterolemia increases Abeta production, an effect that is associated with increased levels of BACE1 and RAGE and reduced levels of IDE and LRP-1. These results suggest that reducing Abeta accumulation in the brain may require strategies that combine reduction of generation and transport of Abeta in addition to acceleration of degradation and clearance of this peptide.
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58202, United States.
R P
RP
Jaya Prasanthi
Eric
E
Schommer
Sarah
S
Thomasson
Alex
A
Thompson
Gwen
G
Feist
Othman
O
Ghribi
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications / Q000209:etiology / Q000378:metabolism*; D007339:Insulysin / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008297:Male; D011817:Rabbits; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002791:Cholesterol, Dietary; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D007339:Insulysin