Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.

TitleDeletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.
Publication TypeJournal Article
Year of Publication2005
AuthorsWahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR, Paul SM, Holtzman DM
JournalJ Biol Chem
Date Published2005 Dec 30
KeywordsAlzheimer Disease, Amyloid, Amyloid beta-Peptides, Animals, Apolipoproteins E, ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Blotting, Western, Brain, Enzyme-Linked Immunosorbent Assay, Gene Deletion, Heterozygote, Hippocampus, Mice, Mice, Transgenic, Models, Genetic, Protein Structure, Tertiary, Thiazoles, Time Factors

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.

Alternate JournalJ. Biol. Chem.
PubMed ID16207708
Grant ListAG11355 / AG / NIA NIH HHS / United States
AG13956 / AG / NIA NIH HHS / United States