Involvement of the mTORC1 and mTORC2 complexes in the cognitive deficits in an animal model of Alzheimers disease

• Grant number: 24/02166-8
• Support Opportunities: Regular Research Grants
• Duration: December 01, 2024 - November 30, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Convênio/Acordo: CNPq
• Principal Investigator: Luiz Roberto Giorgetti de Britto
• Grantee: Luiz Roberto Giorgetti de Britto
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 22/14820-9 - Possible neuroprotection strategies in Parkinson's Disease, AP.R

Abstract

This proposal discusses the global increase in the prevalence of dementia, with a specific focus on Alzheimer's Disease (AD) due to the aging population and the urgent need to develop preventative strategies and effective treatments. It is estimated that there are around 50 million cases of dementia, with expectations of a significant rise by the year 2050. AD, as the leading cause of dementia, poses a global challenge and is inherently linked to the aging process. Projections suggest that neurodegenerative diseases will surpass cancer to become the second leading cause of death by 2040. The primary aim of this research is to explore the complex relationship between AD and the mTOR pathway, with the ultimate goal of elucidating the underlying molecular and cellular mechanisms of interaction between the different mTOR complexes, mTORC1 and mTORC2, in the progression of AD. To achieve this, the study proposes to assess the role these complexes play in neuronal degeneration and cognitive deficits through the use of an Alzheimer's disease animal model in conjunction with the inhibition or deletion of each mTOR complex. Practically, the methodology includes treating mice, serving as AD models, with specific inhibitors or genetic deletion of the mTORC1 and mTORC2 complexes, and evaluating the cognitive abilities of these animals through appropriate tests. Additionally, the accumulation of A², hyperphosphorylated tau protein, genetic expression, and immunohistochemical profiling of key proteins in the PI3K/Akt/mTOR and AMPK/mTOR/ULK1 pathways in the hippocampus will be quantified. This investigation is expected to unequivocally demonstrate the direct contribution of mTOR pathway dysregulation to the pathogenesis of AD, highlighting the distinct roles of the mTORC1 and mTORC2 complexes in the development of the disease. Furthermore, it is anticipated that the genetic deletion of key mTOR complex proteins will differentiate the individual contributions of each complex to the pathogenesis of neuronal death and AD development, providing significant insights for a better understanding of cognitive dysfunction associated with the disease. (AU)