The effects of ABCA1 on cholesterol efflux and Abeta levels in vitro and in vivo.
ABCA1 promotes cholesterol efflux from cells and is required for maintaining plasma cholesterol levels. Cholesterol homeostasis is important in the production of beta-amyloid (Abeta), a peptide that is overproduced in Alzheimer's disease (AD). Overexpression of ABCA1 can be achieved by stimulating Liver X Receptors (LXR), and changes in Abeta have been reported after LXR stimulation in vitro. To determine whether ABCA1 could alter endogenous Abeta levels, we used two different in vivo systems. We first examined the effects of an LXR agonist (TO-901317) on wild-type mice and found an increase in brain ABCA1 and apoE levels, which caused an increase in plasma cholesterol. This was accompanied by a decrease in brain Abeta levels. We then examined endogenous Abeta levels in ABCA1 knockout mice and found that, despite having no ABCA1, lowered brain apoE levels, and lowered plasma cholesterol, there was no change in Abeta levels. To assess these in vivo models in an in vitro system, we designed a model in which cholesterol transport via ABCA1 (or related transporters) was prevented. Switching off cholesterol efflux, even in the presence of TO-901317, caused no change in Abeta levels. However, when efflux capability was restored, TO-901317 reduced Abeta levels. These data show that promoting cholesterol efflux is a viable target for Abeta reducing strategies; however, knockout of cholesterol transporters is not sufficient to alter Abeta in vitro or in vivo.
Burns
Mark P
MP
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA.
Vardanian
Lilit
L
Pajoohesh-Ganji
Ahdeah
A
Wang
Lili
L
Cooper
Matthew
M
Harris
Donnie C
DC
Duff
Karen
K
Rebeck
G William
GW
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D013449:Sulfonamides; C577836:ABCA1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides