Project Portugal 2030

Summary

The MiDA-C42 project posits a pivotal role for Cdc42, a member of the RhoGTPases, in regulating the microglial cytoskeleton, thereby influencing synaptic remodeling and cognitive performance in the aging brain. This hypothesis builds on preliminary results (see Annex) and our previous studies highlighting the distinct roles of RhoGTPases in microglial function, particularly in the context of neuroinflammation, cognitive behavior, and neurodegeneration [4-6]. Aging-related alterations in the microglial cytoskeleton, particularly the actin cytoskeleton, are crucial for brain aging. The MiDA-C42 project aims to understand the specific role of Cdc42 in microglial aging, an underexplored area critical for brain health and plasticity during aging. The main aim of the MiDA-C42 project is to elucidate the roles of Cdc42 in microglia, particularly its impact on brain plasticity across the aging spectrum. This includes understanding the molecular mechanisms governed by Cdc42 in microglial homeostasis and its effects on synaptic remodeling and cognitive performance during aging. Distinct objectives include: i) the study of Cdc42-dependent Microglial Dynamics and Molecular Signatures by investigating the role of Cdc42 in microglial homeostasis and its impact on molecular mechanisms using advanced intravital two-photon imaging and quantitative phosphoproteomics profiling techniques; ii) understanding Cdc42-dependent Microglia-Synapse Interactions in Age-Dependent Brain Plasticity by examining Cdc42’s role in microglial response to experience-dependent brain plasticity in young and aged mice, focusing on microglia-synapse interactions and their implications for microglia homeostasis; iii) understanding how microglial Cdc42 influences Experience-Dependent Synaptic Remodeling and Cognitive Performance by exploring how microglial Cdc42 affects synaptic remodeling and cognitive performance across different age groups, correlating synaptic architecture and function with cognitive outcomes; iv) using Integrative Correlative Analyses with Cognitive Performance to analyze the relationship between synaptic phosphoproteomics and cognitive performance, employing advanced data analysis techniques for a comprehensive understanding of the role of microglial Cdc42 on the aging process at the cellular and molecular level. By employing a multi-disciplinary approach integrating molecular analyses, behavioral studies, multi-omics, advanced bioinformatics, and high-end imaging techniques, the MiDA-C42 team will provide significant insights into the roles of Cdc42 in microglia and its impact on aging-related changes in the brain. This will contribute to a deeper understanding of aging and identify potential therapeutic targets for age-related cognitive decline and neurological conditions.