ROS - Scavenging Magnetic Nanozymes with Remote Activation for Alzheimer Disease

• Grant number: 23/06206-1
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2024
• End date: June 30, 2027
• Field of knowledge: Engineering - Biomedical Engineering - Bioengineering
• Agreement: M-ERA.NET
• Principal Investigator: Vanessa de Jesus Rodrigues de Paula
• Grantee: Vanessa de Jesus Rodrigues de Paula
• Principal researcher abroad: Gerardo F Goya
• Institution abroad: Universidad de Zaragoza, Spain
• Host Institution: Instituto de Psiquiatria Doutor Antonio Carlos Pacheco e Silva (IPq). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Orestes Vicente Forlenza

Abstract

Alzheimer's disease (AD) is a neurodegenerative condition and the prevalent cause of dementia worldwide. Although its etiology has not been yet completely clarified, there is growing consensus on its multifactorial nature. Therefore, the need of multi-target strategies is clear, and the current state of the art in nanomaterials is now mature enough to offer flexible platforms to develop multi-target biomimetic catalysts. Two key players in AD are the amyloid-beta (A²) and hyperphosphorylated tau deposits into the brain, both major sources of reactive oxygen species (ROS). The goal of the ROSSCA project is to develop a new therapeutic approach against AD acting on the diminished activity, recognized in AD patients, of some of the antioxidant enzymes that maintain the redox balance in brain's tissue. For that purpose, we will produce and test a multifunctional, magnetically triggerable nanoplatform, designed to mimic the ROS-scavenging enzymes Catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) relevant to Alzheimer Disease. We aim to deliver these 'nanozymes' with a final readiness level that makes them apt for preclinical trials. The readiness level will be achieved through a series of in-depth testsby each partner of the Consortium on their toxicological safety, their neuroprotective action in hippocampal primary neurons and their efficacy in a rat model of AD. The magnetic nanozymes (MNZs) will be designed to have a reduced graphene oxide (rGO) with specific active centres (metal atoms) bonded with atomic local coordination that mimics those to the corresponding natural enzymes to provide the biocatalytic action. The magnetic core will supply the ability for power absorption under remote ac magnetic fields, aiming local stimulation of the catalytic centres at the surface. The Consortium will be constituted by four internationally renowned partners with the core expertise to deliver a preclinical ready-to-test level of novel MNZs. The partners of ROSSCA project have the skills and experience in a) physics and materials science for design and production of the MNZs, b) genetic toxicology and toxicological profiling for safety assessment, c) molecular biology for their neuroprotective efficacy on primary hippocampal neurons, and d) neurophysiology for performance tests in AD rat models. The novel approach of local activation of the catalytic centers through magnetically actuated nanozymes (MNZs) will allow matching the catalytic efficiency of biological enzymes, without the deleterious effects of denaturalization occurring in their natural counterparts. As such, the new protocols are expected to be potentially transferrable to other neurodegenerative diseases. The proof-of-concept of this new therapeutic approach on AD models will start at TRL3 and span the materials and protocols validation at TRL4. The Consortium will work in collaboration with companies from the technological areas of biomedical devices, biomimetic microplatforms and synthesis at large scale, i.e., those industrial players that will be needed for transferring the main deliverables from ROSSCA to the preclinical level. The outcomes from ROSSCA are expected to provide a breakthrough not only in fundamental research on biocatalytic mechanisms, but also applications in preclinical protocols for dose-controlled antioxidant activity and minimally invasive therapies against AD and other neurodegenerative diseases of the central nervous system. (AU)