Study Of Seeding And Cross-seeding Aggregations Between Amyloid Peptides

Amyloidosis is thought to be the cause of many protein conformational diseases.Amyloid proteins can promote homologous/heterologous proteins to aggregate by seeding or cross-seeding.Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two common protein conformational diseases.Misfolding and aggregation of amyloid β-protein(Aβ)and human islet amyloid polypeptide(h IAPP)are thought to be the main cause of AD and T2 DM.In the brain of AD patients,there are many Aβ spciese with different lengths.The N-terminal truncated peptide Aβ11-40/42 is abundant in AD brain,and located in the core region of senile plaques.Therefore,it may play an important role in the pathogenesis of AD,but at present,there are few studies on Aβ11-40/42.On the other hand,h IAPP can penetrate the blood-brain-barrier and co-aggregate with Aβ.The researches on the interaction between Aβ and its truncated peptides,Aβ and h IAPP were mainly conducted in a solution environment,but no studies conducted on the solid surface have been reported.In order to determine the effect of Aβ11-40 on Aβ40 and elucidate its role in the pathogenesis of AD,this study used Th T fluorescence method,atomic force microscopy,circular dichroism,quartz crystal microbalance and cell toxicity experiments to study the seeding and cross-seeding aggregations of Aβ40 and its N-terminal-truncated Aβ11-40 in the solution and on the surfaces of chips with immobilized seeds.The results showed that Aβ40 and Aβ11-40 aggregates could seed both homologous and heterologous aggregations of the two monomers.However,the capability and characteristics of the seeding(homologous aggregation)and cross-seeding(heterologous aggregation)were significantly different.Aβ40 seeds showed stronger acceleration effects on the aggregations than Aβ11-40 seeds and induced β-sheet-rich fibrous aggregates of similar cytotoxicities for the two monomers.By contrast,Aβ11-40 seeds led to different aggregation pathways of Aβ40 and Aβ11-40.Pure Aβ11-40 aggregates had higher toxicity than Aβ40 aggregates,and as seeds,Aβ11-40 seeds induced Aβ40 to form aggregates of higher cytotoxicity.At the same time,the seeding and cross-seeding aggregations of Aβ40 and h IAPP on the surfaces of chips with immobilized seeds also have been investigated.The results indicate that the binding rate of Aβ40 and h IAPP on homologous seeds is higher than that on heterologous seeds.Aβ40 undergoes similar structural changes on the surface of immobilized Aβ40 and h IAPP seeds.In addition,Aβ40 and h IAPP monomers can co-aggregate,and when the ratio of the two is 1:1,the aggregation and elongation rate is the highest.This study demonstrates that heterologous seeds have significant influence on the process of amyloid aggregation,the structure and toxicity of aggregates.It provides a basis for revealing the pathogenesis of AD and the relationship between AD and T2DM.