ABSTRACT
Evidence suggests that environmental and dietary factors may contribute to the pathogenesis of Parkinson's disease (PD). High dietary intake of cholesterol is such a factor that has been shown to increase or decrease the risk of PD. However, because circulating cholesterol does not cross the blood-brain barrier, the mechanisms linking dietary cholesterol to the pathogenesis of PD remain to be understood. In contrast to cholesterol, the oxidized cholesterol metabolites (oxysterols), 24S-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), can cross the blood-brain barrier and may place the brain at risk of degeneration. In this study, we incubated the human neuroblastoma SH-SY5Y cells for 24 h with 24-OHC, 27-OHC, or a mixture of 24-OHC plus 27-OHC, and have determined effects on tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis) levels, alpha-synuclein levels, and apoptosis. We demonstrate that while 24-OHC increases the levels of tyrosine hydroxylase, 27-OHC increases levels of alpha-synuclein, and induces apoptosis. Our findings show for the first time that oxysterols trigger changes in levels of proteins that are associated with the pathogenesis of PD. As steady state levels of 24-OHC and 27-OHC are tightly regulated in the brain, disturbances in these levels may contribute to the pathogenesis of PD.
Subject(s)
Apoptosis/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Hydroxycholesterols/pharmacology , Tyrosine 3-Monooxygenase/metabolism , alpha-Synuclein/metabolism , Analysis of Variance , Apoptosis/physiology , Cell Line, Tumor , Dopamine/metabolism , Drug Combinations , Humans , In Situ Nick-End Labeling/methods , L-Lactate Dehydrogenase/metabolism , Neuroblastoma/metabolism , Norepinephrine/metabolism , Tetrazolium Salts , ThiazolesABSTRACT
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.
Subject(s)
Alzheimer Disease/etiology , Amyloid beta-Peptides/metabolism , Brain/metabolism , Hypercholesterolemia/metabolism , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Brain/enzymology , Cholesterol, Dietary , Disease Models, Animal , Hypercholesterolemia/complications , Hypercholesterolemia/etiology , Insulysin/metabolism , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Male , Rabbits , Receptor for Advanced Glycation End Products , Receptors, Immunologic/metabolismABSTRACT
Hypercholesterolemia increases levels of beta-amyloid (Abeta), a peptide that accumulates in Alzheimer's disease brains. Because cholesterol in the blood does not cross the blood brain barrier (BBB), the link between circulating cholesterol and Abeta accumulation is not understood. In contrast to cholesterol, the oxidized cholesterol metabolite 27-hydroxycholesterol can cross the BBB, potentially increasing Abeta levels. However, the mechanisms by which cholesterol or 27-hydroxycholesterol regulate Abeta levels are not known. The insulin-like growth factor-1 (IGF-1) regulates the glycogen-synthase kinase-3alpha (GSK-3alpha) and the insulin degrading enzyme (IDE). While GSK-3alpha increases Abeta production, IDE is a major Abeta-degrading enzyme. We report here that feeding rabbits with a cholesterol-enriched diet increases Abeta levels in the hippocampus, an effect that is associated with reduced IGF-1 levels. 27-hydroxycholesterol also increases Abeta and reduces IGF-1 levels in organotypic hippocampal slices from adult rabbits. We suggest that hypercholesterolemia-induced Abeta accumulation may be mediated by 27-hydroxycholesterol, involving IGF-1 signaling.
