title: Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the alpha-secretase pathway.
abstract: The cholesterol 24-hydroxylase encoded by the gene CYP46 is expressed almost exclusively in central nervous system (CNS) neurons and catalyzes the formation of 24S-hydroxycholesterol (24S-OHC) from cholesterol. This conversion corresponds to a major pathway for excretion of excess cholesterol from the brain. There is a significant flux of another oxysterol, 27-hydroxycholesterol (27-OHC) from the circulation into the brain. Polymorphisms within the CYP46A1 gene have been associated with Alzheimer's disease (AD) incidence. In this study, we examined the effects of 24S-OHC and 27-OHC on the alpha- and beta-secretase activity in the human neuroblastoma cell line SH-SY5Y. Furthermore, we examined the effects of the two oxysterols on the levels of extra- and intracellular proteins of secreted APPalpha (sAPPalpha). Our findings suggest that 24S-OHC may exert a unique modulatory effect on APP processing and that this oxysterol increases the alpha-secretase activity as well as the alpha/beta-secretase activity ratio. The possibility is discussed that the ratio between 24S-OHC and 27-OHC is of importance for the generation of amyloid in the brain.
authors.affiliation: Division of Clinical Geriatrics, Department of Neurobiology Care Sciences and Society, Karolinska Institutet and Karolinska University, Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Famer
authors.forename: S
authors.initials: S
authors.lastname: Meaney
authors.forename: M
authors.initials: M
authors.lastname: Mousavi
authors.forename: A
authors.initials: A
authors.lastname: Nordberg
authors.forename: I
authors.initials: I
authors.lastname: Björkhem
authors.forename: M
authors.initials: M
authors.lastname: Crisby
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D006888:Hydroxycholesterols / Q000008:administration & dosage*; D009447:Neuroblastoma / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016564:Amyloid beta-Protein Precursor; D006888:Hydroxycholesterols; C044563:24-hydroxycholesterol; D053829:Amyloid Precursor Protein Secretases