title: Site-specific aspartic acid isomerization regulates self-assembly and neurotoxicity of amyloid-β.
abstract: Amyloid-β (Aβ) proteins, which consist of 42 amino acids (Aβ1–42), are the major constituent of neuritic plaques that form in the brains of senile patients with Alzheimer’s disease (AD). Several reports state that three aspartic acid (Asp) residues at positions 1, 7, and 23 in Aβ1–42 in the plaques of patients with AD are highly isomerized from the L- to D-form. Using biophysical experiments, the present study shows that simultaneous D-isomerization of Asp residues at positions 7 and 23 (D-Asp(7,23)) enhances oligomerization, fibril formation, and neurotoxic effect of Aβ1–42. In addition, D-isomerization of Asp at position 1 (D-Asp(1)) suppresses malignant effects induced by D-Asp(7,23) of Aβ1–42. These results provide fundamental information to elucidate molecular mechanisms of AD pathogenesis and to develop potent inhibitors of amyloid aggregates and Aβ neurotoxicity.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Sugiki
authors.forename: Naoko
authors.initials: N
authors.lastname: Utsunomiya-Tate
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry*; D002470:Cell Survival; D015195:Drug Design; D006801:Humans; D007536:Isomerism; D009474:Neurons / Q000187:drug effects*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000633:toxicity*; D017433:Protein Structure, Secondary; D051381:Rats
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D001224:Aspartic Acid