Abstract
Most Alzheimer’s disease (AD) cases are late-onset and characterized by the aggregation and deposition of the amyloid-beta (Aβ) peptide in extracellular plaques in the brain. However, a few rare and hereditary Aβ mutations, 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 β-amyloid accumulation, and Aβ 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 Aβ1–42 in vitro and structurally characterized the resulting fibrils using a biophysical approach. This paper reports that wild-type and Italian-mutant Aβ both form fibrils characterized by the cross-β architecture, but with distinct β-sheet organizations, resulting in differences in thioflavin T fluorescence and solvent accessibility. E22K Aβ1–42 oligomers and fibrils both display an antiparallel β-sheet structure, in comparison with the parallel β-sheet structure of wild-type fibrils, characteristic of most amyloid fibrils described in the literature. Moreover, we demonstrate structural plasticity for Italian-mutant Aβ fibrils in a pH-dependent manner, in terms of their underlying β-sheet arrangement. These findings are of interest in the ongoing debate that (1) antiparallel β-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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-015-1983-2) contains supplementary material, which is available to authorized users.
Highlights
The conversion of native and functional peptides or proteins into higher ordered, toxic aggregates, and eventually to amyloid fibrils, is characteristic of many human proteinopathies [1]
Under nearphysiological conditions, E22K Ab1–42 spontaneously forms fibrils comprising stable antiparallel b-sheets, in contrast to WT fibrils that are composed of parallel bsheets, similar to most amyloid fibrils described in the literature [50]
We suggest that the antiparallel b-sheet conformation of E22K Ab fibrils, and maybe other cerebral amyloid angiopathy (CAA)-related Ab peptides, predisposes them to mainly deposit in blood vessel walls, resulting in CAA
Summary
The conversion of native and functional peptides or proteins into higher ordered, toxic aggregates, and eventually to amyloid fibrils, is characteristic of many human proteinopathies [1]. The defining molecular unit of these amyloid fibrils is the cross-b spine that originates from extended b-sheets composed of bstrands that are arranged perpendicular to the fiber axis [3]. The cross-b characteristic is a common structural feature, amyloid fibrils show a great structural variety and can differ in their underlying structure, symmetry, width, twist periodicity, and curvature [4,5,6]. This structural polymorphism can have several molecular origins. Variations in the underlying protofilament substructure can contribute to fibril polymorphism [12, 13]. Despite the highly conserved arrangement of fibrils in a cross-b manner along the elongation axis, fibrils can display considerable heterogeneity and structural polymorphism
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