The role of the hippo pathway in the pathophysiology of type 2 diabetes and Alzheimer's Disease, and effects of MST gene knockout associated with glucose treatment in neuronal model

• Grant number: 24/20186-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2025
• End date: June 30, 2027
• Field of knowledge: Biological Sciences - Genetics - Mutagenesis
• Principal Investigator: Elza Tiemi Sakamoto Hojo
• Grantee: Fernanda Camila Albertin Sanches
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/10039-3 - STUDY OF KEY IRS/PI3K/AKT PATHWAY GENES IN NEUROGENESIS AND CELL SURVIVAL PROCESSES UNDER OXIDATIVE AND NEUROTOXIC STRESS IN HUMAN NEURAL MODELS, AP.R

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia caused primarily by insulin resistance (IR) in tissues. In the early stages of the disease, symptoms are often imperceptible, and as chronic hyperglycemia develops with age, various complications and comorbidities arise, including an increased risk (2 to 5 times) for patients to develop Alzheimer's disease (AD) later in life. AD is a progressive neurodegenerative disease that is difficult to diagnose, primarily affecting the hippocampus, where the dentate gyrus is located. This region contains quiescent neural progenitor cells (NPCs) that can be activated and differentiate into new granular neurons through a process known as adult neurogenesis, playing important roles in cognition. The balance between the activation and inactivation of the hippo pathway is crucial in the differentiation process of NPCs, with evidence in the literature suggesting that this pathway may be constantly activated by hyperglycemia, potentially worsening the health status of patients with T2DM. In this project, we will test the hypothesis that in vitro treatment with high glucose levels interferes with the differentiation of NPCs into mature neurons, particularly, increasing the expression of the MST gene, leading to cell death. Therefore, it is expected that knockout of the MST gene will partially restore cellular damage. Additionally, it is expected that this differential expression can be detected in peripheral blood cells sample from patients with T2DM and/or AD, demonstrating the importance of the pathway in disease progression. The data generated from in vitro and in vivo experiments (from patient samples) will help to understand on how high glucose levels impact the differentiation of NPCs and the influence of the status of activation of the hippo pathway. It is anticipated that important information will be generated, providing relevant contribution on the mechanisms involved in the development and progression of AD in patients who are already affected by T2DM.