Effect of the Novel Amyloid Inhibitor 'anle145c' on Aggregation of Islet Amyloid Polypeptide and how it is Modulated by Membranes

Aggregation of islet amyloid polypeptide (IAPP) in the human pancreas is linked to the pathogenesis of type-II diabetes. Interactions of IAPP with membranes may play an important role in the disease, because membranes may catalyze IAPP aggregation and because amyloid formation of IAPP results in membrane permeabilization, and hence cytotoxicity [1]. In order to control this cytotoxicity, there is an intense focus on the development of amyloid inhibitors. Here, we studied the interaction of a novel amyloid inhibitor “anle145c” [2,3,4] on IAPP aggregation in the absence and presence of model membranes using a range of biophysical techniques. Our results show that in both cases the compound acts as an efficient inhibitor, but that it has a distinctly different mode of action in the presence of membranes. Importantly, similar results were obtained with the structurally related natural inhibitor EGCG but with less efficiency. Our complementary experimental approaches reveal that the inhibitors target a different species in the absence and presence of membranes. We propose a model to explain our findings and we discuss its implications for in-vivo studies on these inhibitors.[1] Engel M et al., PNAS. (2008) - 105:6033.[2] Wagner J et al., Acta Neuropathologica (2013) - 125:795.[3] Levin J et al., Acta Neuropathologica (2014) - 127:779.[4] Wagner J et al., Acta Neuropathologica in press (2015) “Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies”.