Synthesis, aggregation, neurotoxicity, and secondary structure of various A beta 1-42 mutants of familial Alzheimer's disease at positions 21-23.
Cerebral amyloid angiopathy (CAA) due to amyloid beta (A beta) deposition is a key pathological feature of Alzheimer's disease (AD), especially in some form of familial Alzheimer's disease (FAD) including hereditary cerebral hemorrhage with amyloidosis-Dutch type. A beta mainly consists of 40- and 42-mer peptides (Abeta 1-40 and A beta 1-42), which accumulate in senile plaques of AD brains and show neurotoxicity for cultured nerve cells. We synthesized all variant forms of A beta 1-42 associated with reported FAD, such as A21G (Flemish), E22Q (Dutch), E22K (Italian), E22G (Arctic), and D23N (Iowa) along with three potential mutants by one point missense mutation (E22A, E22D, and E22V) in a highly pure form, and examined their ability to aggregate and their neurotoxicity in PC12 cells. The mutants at positions 22 and 23 showed potent aggregative ability and neurotoxicity whereas the potential mutants did not, indicating that A beta 1-42 mutants at positions 22 and 23 play a critical role in FAD of Dutch-, Italian-, Arctic-, and Iowa-types. However, Flemish-type FAD needs alternative explanation except the aggregation and neurotoxicity of the corresponding A beta 1-42 mutant.
Murakami
Kazuma
K
Laboratory of Organic Chemistry in Life Science, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Irie
Kazuhiro
K
Morimoto
Akira
A
Ohigashi
Hajime
H
Shindo
Mayumi
M
Nagao
Masaya
M
Shimizu
Takahiko
T
Shirasawa
Takuji
T
D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000235:genetics* / Q000633:toxicity; D000818:Animals; D052160:Benzothiazoles; D016657:Cerebral Amyloid Angiopathy / Q000209:etiology / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D005562:Formazans / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016716:PC12 Cells; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000235:genetics* / Q000633:toxicity; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005562:Formazans; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C009462:thioflavin T