Two distinct diseases
are associated with the deposition of fibrillar
amyloid-β (Aβ) peptides in the human brain in an age-dependent
fashion. Alzheimer’s disease is primarily associated with parenchymal
plaque deposition of Aβ42, while cerebral amyloid angiopathy
(CAA) is associated with amyloid formation of predominantly Aβ40
in the cerebral vasculature. In addition, familial mutations at positions
22 and 23 of the Aβ 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 Aβ 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 Aβ40-Dutch
and Aβ40-Iowa to form antiparallel structure and compare these
propensities to those of the wild-type Aβ40 and Aβ42 isoforms.
We find that both Aβ40-Dutch and Aβ40-Iowa have strong
propensities to form antiparallel β-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 Aβ peptides. We discuss
these differences with respect to the mechanisms of Aβ fibril
formation in CAA.