Oxysterols and neurodegenerative diseases.
In contrast to their parent molecule cholesterol, two of its side-chain oxidized metabolites are able to cross the blood-brain barrier. There is a concentration-driven flux of 24S-hydroxycholesterol (24S-OHC) from the brain into the circulation, which is of major importance for elimination of excess cholesterol from the brain. The opposite flux of 27-hydroxycholesterol (27-OHC) from the circulation into the brain may regulate a number of key enzymes within the brain. In vitro experiments suggest that the balance between the levels of these two molecules may be of importance for the generation of beta-amyloid peptides. In primary cultures of rat hippocampal cells 27-OHC is able to suppress expression of the activity regulated cytoskeleton-associated protein (Arc), a protein important in memory consolidation which is reduced in patients with Alzheimer's disease (AD). In the present work we explore the possibility that the flux of 27-OHC from the circulation into the brain represents the missing link between AD and hypercholesterolemia, and discuss the possibility that modification of this flux may be a therapeutic strategy. Lastly, we discuss the use of oxysterols as diagnostic markers in neurodegenerative disease.
Björkhem
Ingemar
I
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden. ingemar.bjorkhem@karolinska.se
Cedazo-Minguez
Angel
A
Leoni
Valerio
V
Meaney
Steve
S
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D003598:Cytoskeletal Proteins; D006888:Hydroxycholesterols; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein