Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation.
beta-Amyloid (A beta) deposition in fibril form is the central event in a number of diseases, including Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D). A beta is produced by degradation of a larger amyloid precursor protein (APP). Recently a mutation in the APP gene has been found in HCHWA-D causing a glutamine for glutamic acid substitution at residue 22 of A beta. The influence of this mutation on fibrillogenesis is not known, although it is clear that affected patients have accelerated cerebrovascular amyloid deposition, with disease symptoms early in life. We report the in vitro demonstration of accelerated fibril formation in a 28 residue synthetic peptide homologous to the Dutch variant A beta. Furthermore, in eight residue peptides homologous to A beta the presence of the mutation is necessary for fibril formation. These findings provide a mechanism for accelerated amyloid formation in the Dutch variant of APP.
Department of Pathology, NY University Medical Center, New York 10016.
T
T
Wisniewski
J
J
Ghiso
B
B
Frangione
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000648:ultrastructure*; D005971:Glutamates; D018698:Glutamic Acid; D005973:Glutamine; D008854:Microscopy, Electron; D016253:Microscopy, Immunoelectron; D008969:Molecular Sequence Data; D009154:Mutation; D009210:Myofibrils / Q000648:ultrastructure*; D010455:Peptides / Q000138:chemical synthesis*
D016229:Amyloid beta-Peptides; D005971:Glutamates; D010455:Peptides; D005973:Glutamine; D018698:Glutamic Acid