Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 52, Pages 43236-43242Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M508780200
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- NIA NIH HHS [AG13956, AG11355] Funding Source: Medline
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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 (A beta). 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 A beta, 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 A beta 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 A beta. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo.
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