Isoaspartate formation at position 23 of amyloid beta peptide enhanced fibril formation and deposited onto senile plaques and vascular amyloids in Alzheimer's disease.
Senile plaques and amyloid-bearing vessels consisting of fibrillar amyloid beta peptides (A beta) are characteristic neuropathological features of Alzheimer's disease (AD). A beta undergo spontaneous post-translational modifications, such as isomerization and racemization, at their aspartyl residues in AD brains. Here we present evidence that A beta isomerized at position 23 are deposited on plaques and vascular amyloids using an anti-isomerized A beta antibody. In vitro experiments showed that isomerization at position 23, but not position 7, enhanced aggregation. Furthermore, A beta with the Dutch mutation, but not the Flemish mutation, also showed greatly enhanced aggregation. These results suggest that mutations or modifications at positions Glu 22 and Asp 23 have a pathogenic role in the deposition of A beta. The development and progression of sporadic AD may be accelerated by spontaneous isomerization at position 23 of A beta.
Shimizu
Takahiko
T
Department of Molecular Genetics, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan.
Fukuda
Hiroyuki
H
Murayama
Shigeo
S
Izumiyama
Naoki
N
Shirasawa
Takuji
T
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D001224:Aspartic Acid / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007536:Isomerism; D008297:Male; D008854:Microscopy, Electron; D015394:Molecular Structure; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D001224:Aspartic Acid