Mitochondrial Targeted Nano antioxidants to Treat Alzheimer s Disease

ABSTRACT PROJECT SUMMARY Alzheimer s disease AD is characterized by hyperphosphorylated tau protein which causes impaired axonal transport in neurons In recent years multiple researchers have determined that oxidative stress appears to be a significant early event in the pathogenesis of AD in preclinical AD models and in AD patients We have shown that reducing oxidative stress through quenching of mitochondrial reactive oxygen species ROS results in significant improvements in AD pathology in mice Unfortunately targeting oxidative stress to date has not been efficacious clinically in mitigating AD pathology Dietary antioxidants are low potency require high doses are potentially toxic at those doses and have not proven clinically effective There is thus an urgent clinical need to develop potent stable intracellular antioxidants for the treatment of AD Polyethylene glycol PEG conjugated hydrophilic carbon clusters PEG HCCs are novel nanoparticle antioxidants that convert superoxide to O faster than many single active site catalysts These are also stable soluble and non toxic at moderately high concentrations We have shown that PEG HCCs enter cells and preferentially accumulate at or near mitochondria We hypothesize that PEG HCCs inhibit action of IL via ROS quenching which then prevents increased activity of p and cdk resulting in a normalization of hyperphosphorylated tau and a reduction in AD pathology The PEG HCC technology has been awarded multiple patents Acelerox has obtained the international license to the relevant patents for all fields of use and is set to fully explore and develop the unique properties of this novel nanomaterial in treating Alzheimer s disease In this proposal we seek to conduct key animal experiments to establish proof of principle of this novel therapy in animal models of AD In Aim we will Investigate repeated intranasal administration as a potential route of delivery of PEG HCCs In Aim we will perform a proof of concept experiment to establish efficacy of PEG HCC in mouse model of tauopathy In summary we will evaluate a novel class of nano antioxidants the PEG HCCs to effectively reduce ROS in a tau model of AD We are in the unique position to use these highly active bioavailable and selective antioxidant nanomaterials to test the hypothesis that oxidative stress is a viable therapeutic option in treating AD and also begin to assess the mechanisms of improvement in a pre clinical system The extensive data generated using these nanoparticles suggest that they are taken up by cells and targeted to mitochondria the primary source of antioxidants and appear to be well tolerated NARRATIVE Recent research has revealed that the pathology of Alzheimer s disease AD is strongly associated with overproduction of intracellular toxic oxygen species resulting is an urgent clinical search for a potent and selective antioxidant drug We have recently developed a highly potent nontoxic and stable nanoparticle antioxidant which has shown promise in mice models of AD Here we propose to perform pivotal proof of concept experiments to demonstrate efficacy of this novel therapeutic approach in animal models of AD and explore clinically relevant dosage routes