4.8 Article

Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease

Journal

JOURNAL OF CLINICAL INVESTIGATION
Volume 118, Issue 2, Pages 671-682

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI33622

Keywords

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Funding

  1. NIA NIH HHS [R01 AG013956, AG13956, R37 AG013956] Funding Source: Medline
  2. NICHD NIH HHS [HD047396, K08 HD047396-03, K08 HD047396] Funding Source: Medline
  3. NIDDK NIH HHS [P30 DK079333] Funding Source: Medline

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APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1(-/-) mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe(-/-) mice: there was significantly less amyloid beta-peptide (A beta) deposition, a redistribution of A beta to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S-positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.

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