RESUMO
Two distinct diseases are associated with the deposition of fibrillar amyloid-ß (Aß) peptides in the human brain in an age-dependent fashion. Alzheimer's disease is primarily associated with parenchymal plaque deposition of Aß42, while cerebral amyloid angiopathy (CAA) is associated with amyloid formation of predominantly Aß40 in the cerebral vasculature. In addition, familial mutations at positions 22 and 23 of the Aß sequence can enhance vascular deposition in the two major subtypes of CAA. The E22Q (Dutch) mutation is associated with CAA type 2, while the D23N (Iowa) mutation is associated with CAA type 1. Here we investigate differences in the formation and structure of fibrils of these mutant Aß peptides in vitro to gain insights into their biochemical and physiological differences in the brain. Using Fourier transform infrared and nuclear magnetic resonance spectroscopy, we measure the relative propensities of Aß40-Dutch and Aß40-Iowa to form antiparallel structure and compare these propensities to those of the wild-type Aß40 and Aß42 isoforms. We find that both Aß40-Dutch and Aß40-Iowa have strong propensities to form antiparallel ß-hairpins in the first step of the fibrillization process. However, there is a marked difference in the ability of these peptides to form elongated antiparallel structures. Importantly, we find marked differences in the stability of the protofibril or fibril states formed by the four Aß peptides. We discuss these differences with respect to the mechanisms of Aß fibril formation in CAA.