The Stress-Alzheimer's Nexus: Unraveling the Microglial Mitochondrial Roles.

• Grant number: 24/02397-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: July 01, 2024
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Carolina Demarchi Munhoz
• Grantee: João Lucas de Sousa Peres
• Supervisor: Amalia Dolga
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Groningen, Netherlands
• Associated to the scholarship: 22/16523-1 - The influence of chronic unpredictable stress on oligodendrocyte function in the hippocampus and medial prefrontal cortex on memory processes, BP.DD

Abstract

Neuroinflammation is a crucial factor in the development of neurologic diseases such as Alzheimer's disease (AD). Microglia play an essential role in the neuroinflammatory process since they can produce pro-inflammatory cytokines and are also responsible for amyloid beta clearance in AD patients. Mitochondrial dysfunction can trigger the release of mitochondrial damage-associated molecular patterns (mtDAMPs) identified by microglial immune receptors, thereby contributing to the progression of neuroinflammation. Midkine, a heparin-binding growth factor highly expressed in an inflammatory microenvironment, modulates microglial function, and preliminary proteomic data from Prof. Amalia's laboratory using Alzheimer's disease brains detected a positive correlation between MDK and amyloid beta expression. While increasing research reveals interconnections between these processes, substantial gaps persist in understanding the underlying mechanisms. Also, it has already been described that prolonged periods of stress can affect inflammatory-related and neurological disorders, and our research group has demonstrated that chronic unpredictable stress in rats further increases some aspects of LPS-induced neuroinflammation, such as NF-kB activation and IL-1b and TNF in the hippocampus and medial prefrontal cortex. However, little is known about the influence of stress hormones and MDK modulating microglia in AD. Therefore, in this BEPE project, we aim to study the influence of glucocorticoid, the stress hormone, in 1) MDK expression in microglia and human brain samples, 2) microglia phagocytosis and metabolism, and 3) to understand the impact of MDK modulation in microglia function. We intend to use brain samples from AD patients to answer aim 1 and an in vitro model of human pluripotent stem cell-derived microglia to answer aims 1, 2, and 3. These results will produce valuable insights into stress modulation in AD pathology and contribute to developing new potential therapies.