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Journal of Lipid Research, Vol. 45, 186-193, January 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease

Maura Heverin^*, Nenad Bogdanovic, Dieter Lütjohann, Thomas Bayer^**, Irina Pikuleva, Lionel Bretillon^1,*, Ulf Diczfalusy^*, Bengt Winblad and Ingemar Björkhem^2,*

^* Divisions of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden
Geriatrics, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden
Department of Clinical Pharmacology, University of Bonn, Bonn, Germany
^** Department of Psychiatry, Division of Neurobiology, University of the Saarland, Homburg/Saar, Germany
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX

² To whom correspondence should be addressed. e-mail: Ingemar.Bjorkhem{at}hs.se

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.

Supplementary key words cerebral cholesterol • cholesterol 24S-hydroxylase • sterol 27-hydroxylase • oxysterols

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