E Hubin, S Deroo , Kaminski-Schierle G S, Kaminski CF, Serpell L, Subramaniam V, Nuland N v, Broersen K, Raussens V, Sarroukh R, Two distinct β-sheet structures in Italian mutant amyloid-beta fibrils: a potential link to different clinical phenotypes, Cellular and Molecular Life Sciences 2015 1-15 DOI: 10.1007/s00018-015-1983-2 |
Most Alzheimer’s disease (AD) cases are late onset and characterized by the aggregation and deposition of the amyloid-beta (Ab) peptide in extracellular plaques in the brain. However, a few rare and hereditary Abmutations, such as the Italian Glu22-to-Lys (E22K) mutation, guarantee the development of early-onset familial AD. This type of AD is associated with a younger age at disease onset, increased b-amyloid accumulation, and Ab deposition in cerebral blood vessel walls, giving rise to cerebral amyloid angiopathy (CAA). It remains largely unknown how the Italian mutation results in the clinical phenotype that is characteristic of CAA. We therefore investigated how this single point mutation may affect the aggregation of Ab1–42 in vitro and structurally characterized the resulting fibrils using a biophysical approach. This paper reports that wild-type and talianmutant Ab both form fibrils characterized by the cross-b architecture, but with distinct b-sheet organizations, resulting in differences in thioflavin T fluorescence and solvent accessibility. E22K Ab1–42 oligomers and fibrils both display an antiparallel b-sheet structure, in comparison with the parallel b-sheet structure of wild-type fibrils, characteristic of most amyloid fibrils described in the literature. Moreover, we demonstrate structural plasticity for Italian-mutant Ab fibrils in a pH-dependent manner, in terms of their underlying b-sheet arrangement. These findings are of interest in the ongoing debate that (1) antiparallel b-sheet structure might represent a signature for toxicity, which could explain the higher toxicity reported for the Italian mutant, and that (2) fibril polymorphism might underlie differences in disease pathology and clinical manifestation.