Amyloid aggregation and deposition of human islet amyloid polypeptide at membrane interfaces

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Abstract

Amyloid deposition of human islet amyloid polypeptide (hIAPP) within the islets of Langerhans is a pathological feature of type 2 diabetes mellitus. Substantial evidence indicates that the membrane-mediated aggregation and subsequent deposition of hIAPP are linked to dysfunction and death of pancreatic β-cells, but the molecular processes of hIAPP deposition are poorly understood. In this study, we examined the membrane-mediated aggregation and deposition of hIAPP at supported planar lipid bilayers with and without raft components (i.e. cholesterol and sphingomyelin) to provide insight into hIAPP-induced membrane dysfunction. The adsorption of hIAPP onto the bilayers was studied using a quartz crystal microbalance with dissipation monitoring, which showed enhanced accumulation of the peptide onto the bilayer containing raft components. Microscope observations demonstrated the growth of the aggregates formed from the membrane-adsorbed hIAPP. The examination of the membrane interfaces revealed that hIAPP aggregates retained the ability to associate with the membranes during the aggregation process, resulting in insertion of the aggregates into the bilayers. We also report the inhibitory effect of insulin on the hIAPP deposition. These findings demonstrate the aggregation of hIAPP at the membrane interfaces leading to amyloid deposits associated with the membrane and suggest a role for insulin in hIAPP deposition. A presumed mechanism regulating hIAPP deposition at the membrane interfaces is discussed.

We report the membrane-mediated deposition of islet amyloid polypeptide (hIAPP) onto model membranes. The examination of the membrane interfaces revealed that hIAPP aggregates retained the ability to associate with the membranes during the aggregation process, resulting in the insertion of the aggregates into the bilayers. A presumed mechanism regulating hIAPP deposition at the membrane interface is discussed.

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