Abstract
Formation of polymorphic amyloid fibrils is a common feature in neurodegenerative diseases involving protein aggregation. In Alzheimer’s disease, different fibril structures may be associated with different clinical sub-types. Structural basis of fibril polymorphism is thus important for understanding the role of amyloid fibrils in the pathogenesis and progression of these diseases. Here we studied two types of Aβ42 fibrils prepared under quiescent and agitated conditions. Quiescent Aβ42 fibrils adopt a long and twisted morphology, while agitated fibrils are short and straight, forming large bundles via lateral association. EPR studies of these two types of Aβ42 fibrils show that the secondary structure is similar in both fibril polymorphs. At the same time, agitated Aβ42 fibrils show stronger interactions between spin labels across the full range of the Aβ42 sequence, suggesting a more tightly packed structure. Our data suggest that cross-strand side chain packing interactions within the same β-sheet may play a critical role in the formation of polymorphic fibrils.
Highlights
Formation of polymorphic amyloid fibrils is a common feature in neurodegenerative diseases involving protein aggregation
In Alzheimer’s disease, different fibril polymorphs are found in patients with different clinical subtypes[7,8], and these polymorphs can propagate their own conformations in transgenic animal models, as prion strains[9,10]
We aim to study the structural details in polymorphic Aβ42 fibrils using site-directed spin labeling and EPR spectroscopy
Summary
Formation of polymorphic amyloid fibrils is a common feature in neurodegenerative diseases involving protein aggregation. Our data suggest that cross-strand side chain packing interactions within the same β-sheet may play a critical role in the formation of polymorphic fibrils. Using solid-state NMR, Xiao et al.[11], Wälti et al.[12], and Colvin et al.[13] reported a common S-shaped structure for residues 17–42 It appears that the same fibril polymorph was obtained in these three studies. In the parallel in-register β-sheet structure, the fibril samples of a protein spin-labeled at the same residue position leads to the cross-strand stacking of the spin label side chain. EPR data show that these fibril polymorphs are similar at secondary structure level, but differ in the strength of side chain packing. The difference in side chain packing may determine the degree of twist in β-sheets, forming the molecular basis of fibril polymorphism
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