title: Hypercholesterolemia-induced Abeta accumulation in rabbit brain is associated with alteration in IGF-1 signaling.
abstract: 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.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA.
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.forename: Jaya
authors.initials: J
authors.lastname: Prasanthi R P
authors.forename: Eric
authors.initials: E
authors.lastname: Schommer
authors.forename: Gwen
authors.initials: G
authors.lastname: Feist
authors.forename: Othman
authors.initials: O
authors.lastname: Ghribi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism*; D006888:Hydroxycholesterols / Q000378:metabolism; D006937:Hypercholesterolemia / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007339:Insulysin / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011817:Rabbits; D011897:Random Allocation; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D002791:Cholesterol, Dietary; D017362:Cyclic AMP Response Element-Binding Protein; D006888:Hydroxycholesterols; D019253:Proto-Oncogene Proteins c-bcl-2; D007334:Insulin-Like Growth Factor I; C076996:27-hydroxycholesterol; D002784:Cholesterol; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D007339:Insulysin
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