Amyloid cross-seeding between Aβ and hIAPP in relation to the pathogenesis of Alzheimer and type 2 diabetes

Abstract

Abstract Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease (PMDs) and for explaining a molecular link between different PMDs, including Alzheimer disease (AD) and type 2 diabetes (T2D), AD and Parkinson disease (PD), and AD and prion disease. Among them, AD and T2D are the most prevalent PMDs, affecting millions of people globally, while Aβ and hIAPP are the causative peptides responsible for AD and T2D, respectively. Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Aβ and hIAPP is more biologically responsible for a pathological link between AD and T2D. In this review, we particularly focus on (i) the most recent and important findings of amyloid cross-seeding between Aβ and hIAPP from in vitro, in vivo, and in silico studies, (ii) a mechanistic role of structural compatibility and sequence similarity of amyloid proteins (beyond Aβ and hIAPP) in amyloid cross-seeding, and (iii) several current challenges and future research directions in this less-studied field. Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.