Racemization of the amyloidal β Asp1 residue blocks the acceleration of fibril formation caused by racemization of the Asp23 residue

Abstract

Amyloid β proteins extracted from the amyloid cores of neuritic plaques are considerably racemized at their Asp residues. To assess the impact of d-Asp on amyloid β1–42 conformation and on initiation of amyloid fibril formation, we used wild-type amyloid β1–42 and analogs in which d-Asp was substituted for l-Asp at residues 1, 7, 23, and all combinations of these residues. Amyloid fibril formation was enhanced by d-Asp23; modulation of Asp chirality at N-terminal position 1 blocked this enhancement and modulation at position 7 augmented it. Knowledge of such chirality modifications may help to develop potent inhibitors of amyloid fibril formation.