RT Journal Article
SR Electronic
T1 Specific Loss of Brain ABCA1 Increases Brain Cholesterol Uptake and Influences Neuronal Structure and Function
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3579
OP 3589
DO 10.1523/JNEUROSCI.4741-08.2009
VO 29
IS 11
A1 Joanna M. Karasinska
A1 Franz Rinninger
A1 Dieter Lütjohann
A1 Piers Ruddle
A1 Sonia Franciosi
A1 Janine K. Kruit
A1 Roshni R. Singaraja
A1 Veronica Hirsch-Reinshagen
A1 Jianjia Fan
A1 Liam R. Brunham
A1 Nagat Bissada
A1 Rajasekhar Ramakrishnan
A1 Cheryl L. Wellington
A1 John S. Parks
A1 Michael R. Hayden
YR 2009
UL http://www.jneurosci.org/content/29/11/3579.abstract
AB 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.