Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.
24S-hydroxycholesterol is a side-chain oxidized oxysterol formed in the brain that is continuously crossing the blood-brain barrier to reach the circulation. There may be an opposite flux of 27-hydroxycholesterol, which is formed to a lower extent in the brain than in most other organs. Here we measured cholesterol, lathosterol, 24S- and 27-hydroxycholesterol, and plant sterols in four different brain areas of deceased Alzheimer's disease (AD) patients and controls. 24S-hydroxycholesterol was decreased and 27-hydroxycholesterol increased in all the brain samples from the AD patients. The difference was statistically significant in four of the eight comparisons. The ratio of 27-hydroxycholesterol to 24S-hydroxycholesterol was significantly increased in all brain areas of the AD patients and also in the brains of aged mice expressing the Swedish Alzheimer mutation APP751. Cholesterol 24S-hydroxylase and 27-hydroxylase protein was not significantly different between AD patients and controls. A high correlation was observed between the levels of 24S-hydroxycholesterol and lathosterol in the frontal cortex of the AD patients but not in the controls. Most probably the high levels of 27-hydroxycholesterol are due to increased influx of this steroid over the blood-brain barrier and the lower levels of 24S-hydroxycholesterol to decreased production. The high correlation between lathosterol and 24-hydroxycholesterol is consistent with a close coupling between synthesis and metabolism of cholesterol in the frontal cortex of the AD brain.
Heverin
Maura
M
Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Bogdanovic
Nenad
N
Lütjohann
Dieter
D
Bayer
Thomas
T
Pikuleva
Irina
I
Bretillon
Lionel
L
Diczfalusy
Ulf
U
Winblad
Bengt
B
Björkhem
Ingemar
I
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D014867:Water / Q000032:analysis
D006888:Hydroxycholesterols; D014867:Water; C044563:24-hydroxycholesterol; C076996:27-hydroxycholesterol; D006899:Mixed Function Oxygenases