Site-specific aspartic acid isomerization regulates self-assembly and neurotoxicity of amyloid-β

•Simultaneous d-isomerization of Asp7 and Asp23 of Aβ1–42 enhances Aβ1–42 neurotoxicity.•Simultaneous d-isomerization of Asp7 and Asp23 of Aβ1–42 enhances fibril formation.•d-Isomerization of Asp1 suppresses malignant fibrillation and neurotoxicity.•Increase in d-Asp-isomerized Aβ1–42 neurotoxicity is highly correlated with fibril maturation. 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-Asp7,23) enhances oligomerization, fibril formation, and neurotoxic effect of Aβ1–42. In addition, d-isomerization of Asp at position 1 (d-Asp1) suppresses malignant effects induced by d-Asp7,23 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.