QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, March 18, 2009, 29(11):3579-3589; doi:10.1523/JNEUROSCI.4741-08.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Karasinska, J. M. Articles by Hayden, M. R. Search for Related Content PubMed PubMed Citation Articles by Karasinska, J. M. Articles by Hayden, M. R.

 Previous Article  |  Next Article 

Neurobiology of Disease
Specific Loss of Brain ABCA1 Increases Brain Cholesterol Uptake and Influences Neuronal Structure and Function

Joanna M. Karasinska,¹ Franz Rinninger,² Dieter Lütjohann,³ Piers Ruddle,¹ Sonia Franciosi,¹ Janine K. Kruit,¹ Roshni R. Singaraja,¹ Veronica Hirsch-Reinshagen,¹ Jianjia Fan,¹ Liam R. Brunham,¹ Nagat Bissada,¹ Rajasekhar Ramakrishnan,⁴ Cheryl L. Wellington,¹ John S. Parks,⁵ and Michael R. Hayden¹

¹Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4 Canada, ²University Hospital Hamburg Eppendorf, 20246 Hamburg, Germany, ³Institute of Clinical Chemistry and Pharmacology, University of Bonn, 53127 Bonn, Germany, ⁴Division of Biostatistics, Columbia University College of Physicians and Surgeons, New York, New York 10032, and ⁵Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Correspondence should be addressed to Michael R. Hayden, Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Ave, Room 3026, Vancouver, B.C., V5Z 4H4 Canada. Email: mrh{at}cmmt.ubc.ca

The expression of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) in the brain and its role in the lipidation of apolipoproteins indicate that ABCA1 may play a critical role in brain cholesterol metabolism. To investigate the role of ABCA1 in brain cholesterol homeostasis and trafficking, we characterized mice that specifically lacked ABCA1 in the CNS, generated using the Cre/loxP recombination system. These mice showed reduced plasma high-density lipoprotein (HDL) cholesterol levels associated with decreased brain cholesterol content and enhanced brain uptake of esterified cholesterol from plasma HDL. Increased levels of HDL receptor SR-BI in brain capillaries and apolipoprotein A-I in brain and CSF of mutant mice were evident. Cholesterol homeostasis changes were mirrored by disturbances in motor activity and sensorimotor function. Changes in synaptic ultrastructure including reduced synapse and synaptic vesicle numbers were observed. These data show that ABCA1 is a key regulator of brain cholesterol metabolism and that disturbances in cholesterol transport in the CNS are associated with structural and functional deficits in neurons. Moreover, our findings also demonstrate that specific changes in brain cholesterol metabolism can lead to alterations in cholesterol uptake from plasma to brain.

---

Received Oct. 2, 2008; revised Dec. 5, 2008; accepted Jan. 15, 2009.

Correspondence should be addressed to Michael R. Hayden, Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Ave, Room 3026, Vancouver, B.C., V5Z 4H4 Canada. Email: mrh{at}cmmt.ubc.ca

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help