The 39- to 42-residue-long amyloid beta-peptide (A beta-peptide) forms filamentous structures in the neuritic plaques found in the neuropil of Alzheimer's disease patients. The assembly and deposition of A beta-fibrils is one of the most important factors in the pathogenesis of this neurodegenerative disease. Although the structural analysis of amyloid fibrils is difficult, single-molecule methods may provide unique insights into their characteristics. In the present work, we explored the nanomechanical properties of amyloid fibrils formed from the full-length, most neurotoxic A beta 1-42 peptide, by manipulating individual fibrils with an atomic force microscope. We show that A beta-subunit sheets can be mechanically unzipped from the fibril surface with constant forces in a reversible transition. The fundamental unzipping force (similar to 23 pN) was significantly lower than that observed earlier for fibrils formed from the A beta 1-40 peptide (similar to 33 pN), suggesting that the presence of the two extra residues (Ile and Ala) at the peptide's C-terminus result in a mechanical destabilization of the fibril. Deviations from the constant force transition may arise as a result of geometrical constraints within the fibril caused by its left-handed helical structure. The nanomechanical fingerprint of the A beta 1-42 is further influenced by the structural dynamics of intrafibrillar interactions. (c) 2006 Elsevier Inc. All rights reserved.