title: Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.
abstract: Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (epsilon4 > epsilon3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-beta (Abeta) peptide and its conversion to a fibrillar form. To determine the effect of apoE on Abeta 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 Abeta 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 Abeta 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.
authors.affiliation: Department of Neurology, Center for the Study of Nervous System Injury, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: K R
authors.initials: KR
authors.lastname: Bales
authors.forename: T
authors.initials: T
authors.lastname: Tenkova
authors.forename: A M
authors.initials: AM
authors.lastname: Fagan
authors.forename: M
authors.initials: M
authors.lastname: Parsadanian
authors.forename: L J
authors.initials: LJ
authors.lastname: Sartorius
authors.forename: B
authors.initials: B
authors.lastname: Mackey
authors.forename: J
authors.initials: J
authors.lastname: Olney
authors.forename: D
authors.initials: D
authors.lastname: McKeel
authors.forename: D
authors.initials: D
authors.lastname: Wozniak
authors.forename: S M
authors.initials: SM
authors.lastname: Paul
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D052160:Benzothiazoles; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000473:pathology; D016501:Neurites / Q000378:metabolism* / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D052160:Benzothiazoles; D020033:Protein Isoforms; D013844:Thiazoles; C009462:thioflavin T