Polymorphic Aβ42 fibrils adopt similar secondary structure but differ in cross-strand side chain stacking interactions within the same β-sheet

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.

Human cerebral vascular amyloid contains both antiparallel and parallel in-register Aβ40 fibrils

“…The observations that highly twisted fibrils can be observed in the CAA/ad case, the CAA/s case, and in the cryo-EM study suggest that the short, flat generation-0 fibrils adopt this twisted morphology when not interacting with adjacent fibrils or protofibrils. In the case of Aβ42 fibrils that can adopt both twisted fibrils and flat, laterally associated fibrils, electron paramagnetic resonance measurements indicate that the fibrils have the same secondary structure, but the laterally associated fibrils have stronger side chain interactions along the length of the Aβ sequence ( 37 ). In the cryo-EM study on fibrils derived from vascular amyloid ( 36 ), several polymorphs were observed, which the authors proposed had same internal fold and were distinguished by lateral association.…”

Distinguishing the Effect on the Rate and Yield of Aβ42 Aggregation by Green Tea Polyphenol EGCG

“…The EPR spectrum of Aβ42 L34R1 fibrils in the absence of EGCG is characteristic of the parallel in-register β-sheet structure. − The EPR spectra in the presence of 10× and 50× EGCGs have a similar line shape compared to those of the no-EGCG sample (Figure C), suggesting that EGCG did not change the structure of Aβ42 fibrils. Previously, we have obtained the EPR spectra of Aβ42 globulomers (Figure D) and prefibrillar oligomers (Figure E) spin-labeled at the same residue position.…”

Alzheimer’s Aβ42 and Aβ40 form mixed oligomers with direct molecular interactions

“…In the fibrils, the EPR spectral lines are much broader, resulting in greatly reduced spectral amplitude. Another characteristic of the fibril spectrum is that the three EPR resonance lines collapse toward the center line as a result of the spin exchange interaction in the parallel in-register β-sheet structure of Aβ fibrils [ 33,34]. Therefore, even though the Aβ globulomers have a strong tendency to bind to each other, the structures remain unchanged and are very different from the structures in fibrils.…”