TY - JOUR
T1 - Regulation of α- and β-secretase activity by oxysterols
T2 - Cerebrosterol stimulates processing of APP via the α-secretase pathway
AU - Famer, D.
AU - Meaney, S.
AU - Mousavi, M.
AU - Nordberg, A.
AU - Björkhem, I.
AU - Crisby, M.
N1 - Funding Information:
This study was supported by grants from the Swedish Research Council (05817, 03141, and 2015101-3), Swedish Brain Foundation, Brain Power, Swedish Heart-Lung Foundation, Stiftelsen Gamla Tjänarinnor, Thuring Foundation and KI (Karolinska Institutet) Fonder.
PY - 2007/7/20
Y1 - 2007/7/20
N2 - 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 α- and β-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 APPα (sAPPα). Our findings suggest that 24S-OHC may exert a unique modulatory effect on APP processing and that this oxysterol increases the α-secretase activity as well as the α/β-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.
AB - 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 α- and β-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 APPα (sAPPα). Our findings suggest that 24S-OHC may exert a unique modulatory effect on APP processing and that this oxysterol increases the α-secretase activity as well as the α/β-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.
KW - 24S-Hydroxycholesterol
KW - 27-Hydroxycholesterol
KW - APP processing
KW - Alzheimer's disease
KW - Amyloid precursor protein
KW - α/β-Secretase activity ratio
UR - http://www.scopus.com/inward/record.url?scp=34249828178&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2007.05.033
DO - 10.1016/j.bbrc.2007.05.033
M3 - Article
C2 - 17532301
AN - SCOPUS:34249828178
SN - 0006-291X
VL - 359
SP - 46
EP - 50
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -
