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 lessstudied field. Review of amyloid cross-seeding hopefully provides some mechanistic u

nderstanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.