Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease.
APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1(-/-) mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe(-/-) mice: there was significantly less amyloid beta-peptide (Abeta) deposition, a redistribution of Abeta to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S-positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.
Wahrle
Suzanne E
SE
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Jiang
Hong
H
Parsadanian
Maia
M
Kim
Jungsu
J
Li
Aimin
A
Knoten
Amanda
A
Jain
Sanjay
S
Hirsch-Reinshagen
Veronica
V
Wellington
Cheryl L
CL
Bales
Kelly R
KR
Paul
Steven M
SM
Holtzman
David M
DM
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D004195:Disease Models, Animal; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D008074:Lipoproteins