Specific loss of brain ABCA1 increases brain cholesterol uptake and influences neuronal structure and function.
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.
Karasinska
Joanna M
JM
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4 Canada.
Rinninger
Franz
F
Lütjohann
Dieter
D
Ruddle
Piers
P
Franciosi
Sonia
S
Kruit
Janine K
JK
Singaraja
Roshni R
RR
Hirsch-Reinshagen
Veronica
V
Fan
Jianjia
J
Brunham
Liam R
LR
Bissada
Nagat
N
Ramakrishnan
Rajasekhar
R
Wellington
Cheryl L
CL
Parks
John S
JS
Hayden
Michael R
MR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001519:Behavior / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure*; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure*; D013569:Synapses / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics*
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol