Polymorphic A Beta 42 Fibrils Adopt Similar Secondary Structure But Differ In Cross-Strand Side Chain Stacking Interactions Within The Same Beta-Sheet

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 A beta 42 fibrils prepared under quiescent and agitated conditions. Quiescent A beta 42 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 A beta 42 fibrils show that the secondary structure is similar in both fibril polymorphs. At the same time, agitated A beta 42 fibrils show stronger interactions between spin labels across the full range of the A beta 42 sequence, suggesting a more tightly packed structure. Our data suggest that cross-strand side chain packing interactions within the same beta-sheet may play a critical role in the formation of polymorphic fibrils.