Effects of microglial depletion and repopulation in neuronal loss induced by 6-OHDA, a Parkinson's disease model

• Grant number: 17/09909-2
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: October 01, 2017
• End date: July 31, 2018
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Luiz Roberto Giorgetti de Britto
• Grantee: Carolina Parga Martins Pereira
• Supervisor: Kim N. Green
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of California, Irvine (UC Irvine), United States
• Associated to the scholarship: 15/03791-4 - Microglial phenotypes and Parkinson's Disease, BP.DR

Abstract

Parkinson's disease (PD) is considered the second most common neurodegenerative disease in elderly people and is characterized by the presence of motor difficulties, which is a consequence of neuronal degeneration in the substantia nigra pars compacta. A major neurotoxin used for PD study in animal models is 6-hydroxydopamine (6-OHDA), which exerts neurotoxic effects through the production of reactive oxygen species (ROS). ROS release by the enzyme NADPH oxidase (Nox) and microglial activation are early events of neurodegeneration induced by 6-OHDA. Nox is overactivated in PD, which causes redox imbalance and cell damage. Microglial cells are the main components of immune defense in the central nervous system and are derived from monocyte lineage cells. Results with minocycline treatment after 6-OHDA induction in Nox2 knockout (gp91phox-/-) mice demonstrated that the microglia blockade turned these animals more susceptible to developing PD, while, without minocycline treatment, these knockout mice are protected against the neurodegenerative process. As minocycline is not a specific method to eliminate microglia and has effects in other glial cells, we propose to evaluate the neurodegenerative process in this model using the treatment with CSF1R/c-kit inhibitor (PLX3397), which is used to deplete only microglia. Results with PLX3397 showed that when this inhibitor is removed, new microglia cells repopulated the brain in a precise regulated way. Based on those results, we also propose to verify the response of new microglia cells against the 6-OHDA effects, as well as whether the microglia response is dependent of Nox2 modulation.