title: The human amyloid-beta precursor protein770 mutation V717F generates peptides longer than amyloid-beta-(40-42) and flocculent amyloid aggregates.
abstract: One of the familial forms of Alzheimer's disease (AD) encodes the amyloid-beta precursor protein (AbetaPP) substitution mutation V717F. This mutation is relevant to AD research, since it has been utilized to generate transgenic mice models to study AD pathology and therapeutic interventions. Amyloid beta (Abeta) peptides were obtained from the cerebral tissue of three familial AD subjects carrying the AbetaPP V717F mutation. A combination of ultracentrifugation, size-exclusion, and reverse-phase high performance liquid chromatography, tryptic and cyanogen bromide hydrolysis, amino acid analysis, and matrix-assisted laser desorption ionization and surface-enhanced laser desorption ionization mass spectrometry was used to characterize the familial AD mutant Abeta peptides. The AbetaPP V717F mutation, located 4-6 residues beyond the wild-type AbetaPP gamma-secretase cleavage site, yielded longer Abeta peptides with C termini between residues 43 and 54. In the cerebral cortex these peptides aggregated into thin water- and SDS-insoluble amyloid bundles that condensed into flocculent spherical plaques. In the leptomeningeal arteries the amyloid was deposited in moderate amounts and was primarily composed of the shorter and more soluble Abeta species ending at residues 40, 42, and 44. The single V717F mutation in AbetaPP results in distinctive and drastic changes in the length and tertiary structure of Abeta peptides, which appear to be responsible for the earlier clinical manifestations of dementia and death of these patients.
authors.affiliation: The Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City, Arizona 85351, USA. alex.roher@sunhealth.org
authors.forename: Alex E
authors.initials: AE
authors.lastname: Roher
authors.forename: Tyler A
authors.initials: TA
authors.lastname: Kokjohn
authors.forename: Chera
authors.initials: C
authors.lastname: Esh
authors.forename: Nicole
authors.initials: N
authors.lastname: Weiss
authors.forename: Jennifer
authors.initials: J
authors.lastname: Childress
authors.forename: Walter
authors.initials: W
authors.lastname: Kalback
authors.forename: Dean C
authors.initials: DC
authors.lastname: Luehrs
authors.forename: John
authors.initials: J
authors.lastname: Lopez
authors.forename: Daniel
authors.initials: D
authors.lastname: Brune
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Kuo
authors.forename: Martin
authors.initials: M
authors.lastname: Farlow
authors.forename: Jill
authors.initials: J
authors.lastname: Murrell
authors.forename: Ruben
authors.initials: R
authors.lastname: Vidal
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics*; D000818:Animals; D052160:Benzothiazoles; D002540:Cerebral Cortex / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003488:Cyanogen Bromide / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D015151:Immunoblotting; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013844:Thiazoles / Q000737:chemistry; D013997:Time Factors
chemical_list: D000596:Amino Acids; D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010455:Peptides; D013844:Thiazoles; C009462:thioflavin T; D012967:Sodium Dodecyl Sulfate; D003488:Cyanogen Bromide