Amyloid Targeting-Gold Nanoparticles-Assisted X-ray Therapy Rescues Islet β-Cells from Amyloid Fibrils and Restores Insulin Homeostasis.

Abstract

Type-2-diabetes is a metabolic disorder where misfolding and oligomerization of islet amyloid polypeptide (IAPP) around islet-β cells oligomerizes and participates in the pathology. The oligomeric stage is toxic but transitory and leads to the formation of mature amyloid fibrils. The pathological specifics of mature amyloid fibrils are poorly understood. Here, we demonstrate that IAPP amyloids make a gel-like transition, increasing the viscosity of the local microenvironment and encasing and impeding islet-β cells in their ability to sense glucose and release insulin. Using dual-targeted gold nanoparticles (AuNPs) capped with amyloid-fragments of βCasein and anti-IAPP antibodies, we show that X-ray irradiation of AuNPs when bound to IAPP amyloids results in therapeutic remodelling of IAPP amyloids, a reduction in viscosity of the solution, and restoration of glucose/insulin homeostasis. This study establishes that mature IAPP amyloids can participate in the progressive pathology of type-2-diabetes by suppressing insulin responsiveness at the single islet-cell level. It also identifies a therapeutic model of reversal using AuNPs-mediated X-ray therapy, and this approach can be rationally expanded to other amyloid pathologies, such as Alzheimer's and Parkinson's diseases.