No abstract

Aβ42 is the major component of parenchymal plaques in the brain of Alzheimer’s patients, while Aβ40 is the major component of cerebrovascular plaques. Since Aβ40 and Aβ42 co-exist in the brain, understanding the interaction between Aβ40 and Aβ42 during their aggregation is important to delineate the molecular mechanism underlying Alzheimer’s disease. Here, we present a rigorous and systematic study of the cross-seeding effects between Aβ40 and Aβ42. We show that Aβ40 fibril seeds can promote Aβ42 aggregation in a concentration-dependent manner, and vice versa. Our results also suggest that seeded aggregation and spontaneous aggregation may be two separate pathways. These findings may partly resolve conflicting observations in the literature regarding the cross-seeding effects between Aβ40 and Aβ42.

No abstract

Amyloid-β (Aβ) oligomers play a central role in the pathogenesis of Alzheimer's disease. Oligomers of different sizes, morphology and structures have been reported in both in vivo and in vitro studies, but there is a general lack of understanding about where to place these oligomers in the overall process of Aβ aggregation and fibrillization. Here, we show that Aβ42 spontaneously forms oligomers with a wide range of sizes in the same sample. These Aβ42 samples contain predominantly oligomers, and they quickly form fibrils upon incubation at 37°C. When fractionated using ultrafiltration filters, the samples enriched with smaller oligomers form fibrils at a faster rate than the samples enriched with larger oligomers, with both a shorter lag time and faster fibril growth rate. This observation is independent of Aβ42 batches and hexafluoroisopropanol treatment. Furthermore, the fibrils formed by the samples enriched with larger oligomers are more readily solubilized by epigallocatechin gallate, a main catechin component of green tea. These results suggest that the fibrils formed by larger oligomers may adopt a different structure from fibrils formed by smaller oligomers, pointing to a link between oligomer heterogeneity and fibril polymorphism.

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.