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Journal article

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

Wahrle S, Jiang H, Parsadanian M, Hartman R, Bales K, Paul S, Holtzman D ...see all

The Journal of biological chemistry, vol. 280, issue 52 (2005) pp. 43236-42

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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.

Author-supplied keywords

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • ATP-Binding Cassette Transporters: genetics
  • ATP-Binding Cassette Transporters: physiology
  • Alzheimer Disease
  • Alzheimer Disease: genetics
  • Alzheimer Disease: pathology
  • Amyloid
  • Amyloid beta-Peptides
  • Amyloid beta-Peptides: metabolism
  • Amyloid: metabolism
  • Animals
  • Apolipoproteins E
  • Apolipoproteins E: metabolism
  • Blotting
  • Brain
  • Brain: metabolism
  • Brain: pathology
  • Enzyme-Linked Immunosorbent Assay
  • Gene Deletion
  • Genetic
  • Heterozygote
  • Hippocampus
  • Hippocampus: metabolism
  • Hippocampus: pathology
  • Mice
  • Models
  • Protein Structure
  • Tertiary
  • Thiazoles
  • Thiazoles: pharmacology
  • Time Factors
  • Transgenic
  • Western

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Authors

  • Suzanne E Wahrle

  • Hong Jiang

  • Maia Parsadanian

  • Richard E Hartman

  • Kelly R Bales

  • Steven M Paul

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