Structure of amyloid-β (20-34) with Alzheimer’s-associated isomerization at Asp23 reveals a distinct protofilament interface

Fibril formation and characterization of Aβ^20–34 peptides

Six early-onset hereditary Alzheimer’s mutations and two PTMs, including the isomerized Asp23, are localized in the Aβ 1–42 peptide to a region spanning six residues from Ala21 to Ser26 near the center of the peptide (Fig. 1a, b)^17,34,35. The amyloid-forming propensity of segments in this region of Aβ was assessed using a computational method of predicting steric zippers by a threading protocol (ZipperDB³⁶). This method highlights a region of Aβ from Asn27 to Gly37 with high aggregation propensity near the site of Asp23 isomerization (Fig. 1b). To characterize segments containing an isomerized Asp residue at position 23, we utilized synthetic 15 residue peptides spanning the Aβ residues 20–34 (Aβ^20–34) in which Asp23 was substituted with either an L-Asn residue (Iowa mutant; Aβ^{20–34, Asp23Asn}) or an…