The possible neurodegenerative action of GSK-3¿ in the hypothalamus and hippocampus from prediabetic and obese C57BL/6 mice

• Grant number: 24/20027-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2025
• End date: January 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Helena Cristina de Lima Barbosa
• Grantee: Juliana Luiza de Lemos
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Obesity and type 2 diabetes mellitus (T2DM) are chronic conditions that are associated with and responsible for high morbidity worldwide. In Brazil, more than 13 million people have T2DM, and its prevalence increases with the aging population. There is evidence of a close relationship between T2DM and Alzheimer's disease (AD) since both diseases' present insulin resistance in the brain and present similar metabolic dysfunctions. It is known that the kinase GSK3¿, which acts in the pathogenesis of AD and Parkinson's, presents an increase in its protein content during conditions of hyperglycemia, inflammatory processes,and insulin resistance in the central nervous system (CNS). During AD, the increase in GSK-3¿ leads to processes such as tau hyperphosphorylation, structural alterations in APP and specific oxidative stress, leading to the loss of neuronal integrity. In addition, GSK-3¿ regulates the transcription factor Nrf2, amolecular regulator involved in cytoprotecting and cellular antioxidant responses. GSK-3¿ plays a key role in mitochondrial biogenesis, motility, and viability. Our preliminary studies identified a significant increase in GSK-3¿ gene content in thehippocampus from prediabetic and obese mice, which may indicate a possible state of neurodegeneration during T2DM. Based on the above, this project aims to identify possible alterations typical of neurodegenerative processes in the hippocampus and hypothalamus of mice fed a high-fat diet. To this end, we will investigate whether prediabetic and obese mice present CNS alterations common to AD, focusing on GSK-3¿ activity and its possible relationship with mitochondrial dysfunction in specific regions, such as the hippocampus and hypothalamus, both vulnerable to neurodegenerative damage caused by AD. Finally, GSK-3¿ activitywill be assessed by quantifying the ratio between p-ser9-GSK-3¿ and total GSK3¿, and its cellular localization (cytosol, nucleus or mitochondria), which will be investigated by immunofluorescence analysis. The phosphorylation of GSK-3¿ protein targets associated with normal mitochondrial function, such as Nrf2 and VDAC-1, will also have their content evaluated. In addition, the gene expression of proteins associated with neurodegeneration: APP, tau and BACE-1, and withneuroprotection: ADAM-10 and X11-¿, will be quantified. In the end of this project, we will be able to better understand whether, in addition to inflammatory processes and insulin resistance, neurodegeneration processes also occur in the CNS during the development of T2DM, thus providing greater elucidation of the molecular interactions between T2DM and the triggers of neurodegeneration.