Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the alpha-secretase pathway.
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.
Famer
D
D
Division of Clinical Geriatrics, Department of Neurobiology Care Sciences and Society, Karolinska Institutet and Karolinska University, Hospital Huddinge, 14186 Stockholm, Sweden.
Meaney
S
S
Mousavi
M
M
Nordberg
A
A
Björkhem
I
I
Crisby
M
M
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*
D016564:Amyloid beta-Protein Precursor; D006888:Hydroxycholesterols; C044563:24-hydroxycholesterol; D053829:Amyloid Precursor Protein Secretases