Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease

David M. Holtzman, Kelly R. Bales, Tanya Tenkova, Anne M. Fagan, Maia Parsadanian, Leah J. Sartorius, Brian Mackey, John Olney, Daniel McKeel, David Wozniak, Steven M. Paul

Research output: Contribution to journalArticlepeer-review

666 Scopus citations

Abstract

Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (ε4 > ε3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-β (Aβ) peptide and its conversion to a fibrillar form. To determine the effect of apoE on Aβ deposition and AD pathology, we compared APP(V717F) transgenic (TG) mice expressing mouse, human, or no apoE (apoE(-/-)). A severe, plaque-associated neuritic dystrophy developed in APP(V717F) TG mice expressing mouse or human apoE. Though significant levels of Aβ deposition also occurred in APP(V717F) TG, apoE(-/- ) mice, neuritic degeneration was virtually absent. Expression of apoE3 and apoE4 in APP(V717F) TG, apoE(-/-) mice resulted in fibrillar Aβ deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APP(V717F) TG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD.

Original languageEnglish
Pages (from-to)2892-2897
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number6
DOIs
StatePublished - Mar 14 2000

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