Review Oxysterols and neurodegenerative diseases Ingemar Björkhem a, * , Angel Cedazo-Minguez b , Valerio Leoni c , Steve Meaney d a Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, 141 86 Huddinge, Sweden b Neurotec Department, Karolinska Institutet, Karolinska University Hospital, 141 86 Huddinge, Sweden c Division of Biochemistry and Genetics, ‘‘C.Besta” Neurological Institute, Milan, Italy d School of Biological Sciences, Faculty of Science, Dublin Institute of Technology, Dublin, Ireland article info Article history: Received 22 December 2008 Accepted 10 February 2009 Keywords: Blood–brain barrier 24S-Hydroxycholesterol 27-Hydroxycholesterol b-Amyloid Activity regulated cytoskeleton-associated protein CYP27 CYP46 abstract 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-hydrox- ycholesterol (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 mol- ecules may be of importance for the generation of b-amyloid peptides. In primary cultures of rat hippocampal cells 27-OHC is able to suppress expression of the activity regulated cyto- skeleton-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 pos- sibility 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. Ó 2009 Elsevier Ltd. All rights reserved. Contents 1. Brain cholesterol ........................................................................................ 172 1.1. General aspects .................................................................................... 172 1.2. Side-chain oxidized oxysterols ........................................................................ 172 1.3. CYP46 activity and its regulation ...................................................................... 174 2. Biological roles of side-chain oxysterols ...................................................................... 174 2.1. Role of 24S-hydroxycholesterol for the flux of cholesterol from astrocytes to neuronal cells ...................... 174 2.2. Is production of 24S-hydroxycholesterol of importance for memory function? ................................. 175 2.3. Effect of the side-chain oxidized oxysterols on amyloidogenesis ............................................ 175 2.4. Effect of 27-hydroxycholesterol on production of Arc ..................................................... 175 3. Side-chain oxidized oxysterols as biomarkers ................................................................. 175 0098-2997/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mam.2009.02.001 * Corresponding author. Tel.: +46 8 58581235; fax: +46 8 58581260. E-mail address: ingemar.bjorkhem@karolinska.se (I. Björkhem). Abbreviations: 24S-OHC, 24S-hydroxycholesterol; 27-OHC, 27-hydroxycholesterol; Ab, b-amyloid; ABCA1, ATP-binding cassette, subfamily A member 1; ABCG1, ATP-binding cassette, subfamily G member 1; AD, Alzheimer’s disease; APOE, apolipoprotein E; APP, amyloid precursor protein; Arc, activity- regulated cytoskeleton-associated protein; CNS, central nervous system; CSF, cerebrospinal fluid; HDACi, histone deacetylase inhibitor; HMGCR, hydroxyl- methyl-glutaryl coenzyme A reductase; LOAD, late onset AD; LXR, liver X receptor; MRI, magnetic resonance imaging; MS, multiple sclerosis; Nmdar, N-methyl-D-aspartate receptor. Molecular Aspects of Medicine 30 (2009) 171–179 Contents lists available at ScienceDirect Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam