Annexin A5 Directly Interacts with Amyloidogenic Proteins and Reduces Their Toxicity

Protein misfolding is it central mechanism for the development of neurodegenerative diseases and type 2 diabetes mellitus. The accumulation of misfolded alpha-synuclein protein inclusions in the Lewy bodies of Parkinson's disease is thought to play I key role in pathogenesis and disease progression Similarly, the misfolding of the beta-cell hormone human islet amyloid polypeptide (h-IAPP) into toxic oligomers plays a central role in the induction Of beta-cell apoptosis in the context of type 2 diabetes. In this study, we show that annexin A5 plays a role in Interacting with and reducing the toxicity of the amyloidogenic proteins, h-IAPP and alpha-synuclein. We find that annexin A5 is coexpressed in human beta-cells and that exogenous annexin A5 reduces the level of h-IAPP-induced apoptosis in human Islets by similar to 50% and in rodent beta-cells by similar to 90% Experiments with transgenic expression of alpha-synuclein in Caenorhabditis elegans v show that annexin A5 reduces alpha-synuclein inclusions in vivo Using thioflavin T fluorescence. election microscopy, and electron paramagnetic resonance. We provide evidence that substoichiometric amounts of annexin A5 inhibit h-IAPP and alpha-synuclein misfolding and fibril formation We conclude that annexin A5 might act as a molecular safeguard against the formation of toxic amyloid aggregates.