title: Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.
abstract: Apolipoprotein E (apoE) genotype has a major influence on the risk for Alzheimer disease (AD). Different apoE isoforms may alter AD pathogenesis via their interactions with the amyloid beta-peptide (Abeta). Mice lacking the lipid transporter ABCA1 were found to have markedly decreased levels and lipidation of apoE in the central nervous system. We hypothesized that if Abca1-/- mice were bred to the PDAPP mouse model of AD, PDAPP Abca1-/ mice would have a phenotype similar to that of PDAPP Apoe+/- and PDAPP Apoe-/- mice, which develop less amyloid deposition than PDAPP Apoe+/+ mice. In contrast to this prediction, 12-month-old PDAPP Abca -/- mice had significantly higher levels of hippocampal Abeta, and cerebral amyloid angiopathy was significantly more common compared with PDAPP Abca1+/+ mice. Amyloid precursor protein (APP) C-terminal fragments were not different between Abca1 genotypes prior to plaque deposition in 3-month-old PDAPP mice, suggesting that deletion of Abca1 did not affect APP processing or Abeta production. As expected, 3-month-old PDAPP Abca1-/- mice had decreased apoE levels, but they also had a higher percentage of carbonate-insoluble apoE, suggesting that poorly lipidated apoE is less soluble in vivo. We also found that 12-month-old PDAPP Abca1-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble Abeta. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo.
authors.affiliation: Program in Neurosciences, Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Wahrle
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Maia
authors.initials: M
authors.lastname: Parsadanian
authors.forename: Richard E
authors.initials: RE
authors.lastname: Hartman
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Bales
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D052160:Benzothiazoles; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D017434:Protein Structure, Tertiary; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000682:Amyloid; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T