Effect of lysine-28 side-chain acetylation on the nanomechanical behavior of Alzheimer amyloid β25-35 fibrils

Amyloid fibrils are self-associating filamentous Structures formed from the 39- to 42-residue-long amyloid C, peptide (A beta peptide). The deposition of A beta fibrils is one of the most important factors in the pathogenesis, of Alzheimer's disease. A beta 25-35 is a fibril-forming peptide that is thought to represent the biologically M C, active, toxic form of the full-length M peptide. We have recently shown that [3 sheets can be mechanically unzipped from the fibril Surface with constant forces in a reversible transition, and the unzipping forces differ in fibrils composed of different peptides. In the present work, we explored the effect of epsilon-amino acetylation of the Lys28 residue on the magnitude of the unzipping force of A beta 25-35 fibrils. Although the gross Structure of the Lys28-acetylated (A beta 25-35_K28Ac) and wild-type A beta 25-35 (A beta 25-35wt) fibrils were similar, as revealed by atomic force microscopy, the fundamental unzipping forces were significantly lower for A 25-35_K28Ac (20 +/- 4 pN SD) than for A beta 25-35wt (42 9 pN SD). Simulations based oil a simple two-state model suggest that the decreased unzipping forces, caused most likely by steric constraints, are likely due to a destabilized zippered state of the fibril.