Inhibition of the P2X7 purinergic receptor in microglia-mediated neuroinflammation in the in vivo model of Alzheimer's disease and its possible correlation with GSK3

• Grant number: 24/04616-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date until: July 01, 2024
• End date until: November 30, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Alexander Henning Ulrich
• Grantee: Guilherme de Azevedo Carvalho
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases, AP.TEM

Abstract

Several pieces of evidence point to inflammation as a relevant phenomenon in Alzheimer's Disease (AD), promoting alterations in the beta-amyloid (A²) degradation process and in the induction of neuronal death. Studies indicate that microglial activation is involved in both processes. In AD, the presence of A² promotes the activation of microglia with the participation of the P2X7R receptor, promoting the release of pro-inflammatory cytokines such as IL-1². The expression of P2X7R in microglia is widely known, as well as its participation in inflammatory pathways, especially the activation of NLRP3 inflammasomes. In addition, P2X7R acts in the regulation of glycogen synthase kinase 3 (GSK-3), an enzyme that promotes the cleavage of A² proteins, hyperphosphorylation of tau proteins and increased production of TNF-alpha and IL-1b. In this way, inhibition of this receptor promotes neuroprotective action, resulting in a reduction in the cognitive decline seen in rats. Thus, the aim of this study is to evaluate the neuroinflammatory mechanisms mediated by microglia in AD, focusing on the role of P2X7R in pathological processes and cognitive and metabolic functional alterations. To this end, we will use the SAMP-8 (Senescence Accelerated Mouse Prone 8) animal, considered a sporadic AD model. These animals show an accumulation of pro-inflammatory cytokines in the blood plasma as they age, as well as astroglial and microglial activation. Therefore, we will investigate the role of P2X7R in different neuroinflamatory process of AD, which will make it possible to identify tangible treatments for the disease in question. This work will be carried out in partnership with the Department of Physiology and Biophysics (ICB/USP), where the SAMP-8 colony is established and where the behavioral, molecular biology and histological tests will be carried out.