Cations as Switches of Amyloid-Mediated Membrane Disruption Mechanisms: Calcium and IAPP

Disruption of the integrity of the plasma membrane by amyloidogenic proteins is linked to the pathogenesis ofa number of common age-related diseases. Although accumulating evidence suggests that adverse environmental stressorssuch as unbalanced levels of metal ions may trigger amyloid-mediated membrane damage, many features of the molecularmechanisms underlying these events are unknown. Using human islet amyloid polypeptide (hIAPP, aka amylin), an amyloidogenicpeptide associated with b-cell death in type 2 diabetes, we demonstrate that the presence of Ca2þ ions inhibits membranedamage occurring immediately after the interaction of freshly dissolved hIAPP with the membrane, but significantly enhancesfiber-dependent membrane disruption. In particular, dye leakage, quartz crystal microbalance, atomic force microscopy, andNMR experiments show that Ca2þ ions promote a shallow membrane insertion of hIAPP, which leads to the removal of lipidsfrom the bilayer through a detergent-like mechanism triggered by fiber growth. Because both types of membrane-damage mechanismsare common to amyloid toxicity by most amyloidogenic proteins, it is likely that unregulated ion homeostasis, amyloidaggregation, and membrane disruption are all parts of a self-perpetuating cycle that fuels amyloid cytotoxicity.