Insulin Nanogel as New Strategy for the Treatment of Alzheimer’s Disease

Abstract

A growing body of evidence shows that Insulin, Insulin Receptor (IR) and IR signaling are involved in brain cognitive functions and their dysfunction is implicated in neuronal degeneration associated with Alzheimer's disease (AD). Thus, the administration of insulin to the brain could be a strategy for the prevention and treatment of AD disease. With this aim, we have designed, synthesized and characterized a nanogel system (NG) that can be used as substrate for the conjugation of insulin and/or fluorescent molecules relevant for their characterization. In particular, a carboxyl-functionalized poly(N-vinyl pyrrolidone) nanogel system, has been produced by ionizing radiation starting from the polymeric aqueous solution and four insulin molecules per nanogel have been irreversibly attached. Absence of cytotoxicity, oxidative stress and mitochondrial dysfunction support the biocompatibility of the “naked” nanogels. Their hemocompatibility has been demonstrated by hemolysis, coagulation time, leukocyte proliferation and inflammatory response tests. By fluorescence measurements we have demonstrated that the insulin conjugated to the NG (NG-In) is protected by protease degradation and is able to bind and activate insulin receptor, thus triggering insulin signaling via AKT activation. In order to provide more significant evidence of the functionality of the insulin conjugated to the nanoparticles at the body level, the effect of NG-In in reducing the plasma glucose levels in mice has been demonstrated. Neuroprotection of NG-In against dysfunction induced by amyloid β, a peptide mainly involved in AD, has been also verified. Finally, the potential of NG-In to be efficiently transported across the Blood Brain Barrier has been demonstrated in vitro. All together, these results indicate that the synthesized NG-In is a suitable vehicle system for insulin deliver and a very promising tool to develop new therapies for neurodegenerative diseases