ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE.
ABCA1 is an ATP-binding cassette protein that transports cellular cholesterol and phospholipids onto high density lipoproteins (HDL) in plasma. Lack of ABCA1 in humans and mice causes abnormal lipidation and increased catabolism of HDL, resulting in very low plasma apoA-I, apoA-II, and HDL. Herein, we have used Abca1-/- mice to ask whether ABCA1 is involved in lipidation of HDL in the central nervous system (CNS). ApoE is the most abundant CNS apolipoprotein and is present in HDL-like lipoproteins in CSF. We found that Abca1-/- mice have greatly decreased apoE levels in both the cortex (80% reduction) and the CSF (98% reduction). CSF from Abca1-/- mice had significantly reduced cholesterol as well as small apoE-containing lipoproteins, suggesting abnormal lipidation of apoE. Astrocytes, the primary producer of CNS apoE, were cultured from Abca1+/+, +/-, and -/- mice, and nascent lipoprotein particles were collected. Abca1-/- astrocytes secreted lipoprotein particles that had markedly decreased cholesterol and apoE and had smaller apoE-containing particles than particles from Abca1+/+ astrocytes. These findings demonstrate that ABCA1 plays a critical role in CNS apoE metabolism. Since apoE isoforms and levels strongly influence Alzheimer's disease pathology and risk, these data suggest that ABCA1 may be a novel therapeutic target.
Program in Neurosciences, Washington University, St. Louis, Missouri 63110, USA.
Suzanne E
SE
Wahrle
Hong
H
Jiang
Maia
M
Parsadanian
Justin
J
Legleiter
Xianlin
X
Han
John D
JD
Fryer
Tomasz
T
Kowalewski
David M
DM
Holtzman
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000544:Alzheimer Disease; D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry*; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D002490:Central Nervous System / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D051152:Clusterin; D004797:Enzyme-Linked Immunosorbent Assay; D006023:Glycoproteins / Q000378:metabolism; D006579:Heterozygote; D008055:Lipids / Q000737:chemistry*; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D020033:Protein Isoforms; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D008055:Lipids; D008074:Lipoproteins; D018832:Molecular Chaperones; D010743:Phospholipids; D020033:Protein Isoforms; D002784:Cholesterol