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

Suzanne E. Wahrle, Hong Jiang, Maia Parsadanian, Richard E. Hartman, Kelly R. Bales, Steven M. Paul, David M. Holtzman

Research output: Contribution to journalArticlepeer-review

258 Scopus citations

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 β-peptide (Aβ). 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 Aβ, 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 Aβ 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 Aβ. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo.

Original languageEnglish
Pages (from-to)43236-43242
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number52
DOIs
StatePublished - Dec 30 2005

Fingerprint

Dive into the research topics of 'Deletion of Abca1 increases Aβ deposition in the PDAPP transgenic mouse model of Alzheimer disease'. Together they form a unique fingerprint.

Cite this