The Human Amyloid-β Precursor Protein770 Mutation V717F Generates Peptides Longer Than Amyloid-β-(40-42) and Flocculent Amyloid Aggregates

Alex E. Roher, Tyler A. Kokjohn, Chera Esh, Nicole Weiss, Jennifer Childress, Walter Kalback, Dean C. Luehrs, John Lopez, Daniel Brune, Yu Min Kuo, Martin Farlow, Jill Murrell, Ruben Vidal, Bernardino Ghetti

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

One of the familial forms of Alzheimer's disease (AD) encodes the amyloid-β precursor protein (AβPP) 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 (Aβ) peptides were obtained from the cerebral tissue of three familial AD subjects carrying the AβPP 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 Aβ peptides. The AβPP V717F mutation, located 4-6 residues beyond the wild-type AβPP γ-secretase cleavage site, yielded longer Aβ 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 Aβ species ending at residues 40, 42, and 44. The single V717F mutation in AβPP results in distinctive and drastic changes in the length and tertiary structure of Aβ peptides, which appear to be responsible for the earlier clinical manifestations of dementia and death of these patients.

Original languageEnglish
Pages (from-to)5829-5836
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number7
DOIs
StatePublished - Feb 13 2004

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Amyloid
Amyloid beta-Protein Precursor
Alzheimer Disease
Peptides
Mutation
Ionization
Desorption
Cyanogen Bromide
Amyloid Precursor Protein Secretases
Lasers
Amyloid beta-Peptides
Ultracentrifugation
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
High performance liquid chromatography
Pathology
Reverse-Phase Chromatography
Cerebral Cortex
Transgenic Mice
Mass spectrometry
Dementia

ASJC Scopus subject areas

  • Biochemistry

Cite this

The Human Amyloid-β Precursor Protein770 Mutation V717F Generates Peptides Longer Than Amyloid-β-(40-42) and Flocculent Amyloid Aggregates. / Roher, Alex E.; Kokjohn, Tyler A.; Esh, Chera; Weiss, Nicole; Childress, Jennifer; Kalback, Walter; Luehrs, Dean C.; Lopez, John; Brune, Daniel; Kuo, Yu Min; Farlow, Martin; Murrell, Jill; Vidal, Ruben; Ghetti, Bernardino.

In: Journal of Biological Chemistry, Vol. 279, No. 7, 13.02.2004, p. 5829-5836.

Research output: Contribution to journalArticle

Roher, AE, Kokjohn, TA, Esh, C, Weiss, N, Childress, J, Kalback, W, Luehrs, DC, Lopez, J, Brune, D, Kuo, YM, Farlow, M, Murrell, J, Vidal, R & Ghetti, B 2004, 'The Human Amyloid-β Precursor Protein770 Mutation V717F Generates Peptides Longer Than Amyloid-β-(40-42) and Flocculent Amyloid Aggregates', Journal of Biological Chemistry, vol. 279, no. 7, pp. 5829-5836. https://doi.org/10.1074/jbc.M311380200
Roher, Alex E. ; Kokjohn, Tyler A. ; Esh, Chera ; Weiss, Nicole ; Childress, Jennifer ; Kalback, Walter ; Luehrs, Dean C. ; Lopez, John ; Brune, Daniel ; Kuo, Yu Min ; Farlow, Martin ; Murrell, Jill ; Vidal, Ruben ; Ghetti, Bernardino. / The Human Amyloid-β Precursor Protein770 Mutation V717F Generates Peptides Longer Than Amyloid-β-(40-42) and Flocculent Amyloid Aggregates. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 7. pp. 5829-5836.
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