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

Abstract

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

Ca2+ Interacts with Glu-22 of Aβ(1–42) and Phospholipid Bilayers to Accelerate the Aβ(1–42) Aggregation Below the Critical Micelle Concentration

“…71 Surprisingly, studies on the interaction between Aβ and lipid bilayer or cell membrane have largely overlooked the effect of Ca 2+ on the initial adsorption and subsequent accumulation of Aβ peptides at phospholipids, even though such an effect has been noted in the studies of other amyloidogenic species such as IAPP and α-synuclein. 40,41 Our SPR data suggest that Ca 2+ not only strengthens the interaction between Aβ peptides and phospholipids (Figure 2A) but also helps scavenge trace amounts of Aβ molecules at the lipid/solution interface to accelerate Aβ oligomerization/fibrillation ( Figure 4A). These functions are unique of Ca 2+ , as Mg 2+ does not hasten the Aβ adsorption/oligomerization.…”

Islet Amyloid Polypeptide Membrane Interactions: Effects of Membrane Composition

“…An important practical point is that minor variations in buffer or salt composition or concentration have a significant effect on hIAPP membrane interactions, making comparison of studies conducted under different conditions challenging. Low levels of Ca 2+, also have significant effects upon hIAPP amyloid formation in the presence of anionic vesicles, but in this case the mechanism is different and the effects are due to cation binding to the head group of the anionic lipids 82 .…”

Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide

“…However, IAPP is aggregation prone sans the stabilisation of insulin, physiological metal ions, low pH, 1–6 or their complexation with zinc and C-peptide, 7 and accumulating evidence has implicated IAPP amyloid aggregation as a hallmark of pancreatic β-cell death and type-2 diabetes (T2D), a disease impairing millions of people worldwide with profound social and economic implications.…”