Effect of Microglial Depletion in an Alzheimer's Disease Model

• Grant number: 25/14830-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2025
• Status: Discontinued
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luiz Roberto Giorgetti de Britto
• Grantee: Ana Caroline Santos Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 24/06017-7 - Aging-related neurodegenerative disorders: from the cell to the patient, AP.TEM

Abstract

Alzheimer's Disease (AD) is a neurodegenerative disorder. The histopathology of ADis characterized by the accumulation of misfolded proteins, primarily ¿-amyloid andhyperphosphorylated tau. The buildup of these proteins triggers inflammatory eventsin the brain, during which glial cells, particularly microglia, are recruited. For a longtime, the role of microglia in AD was underestimated, but more recent researchshows that these cells exhibit different reactive states that can either contribute to orinhibit the inflammatory process. The exact role of microglia in AD progression is stillnot fully understood. Microglia rely on signaling through the CSF1R(colony-stimulating factor 1 receptor) for their survival. In this study, we will usegenetically modified mice (3xTg-AD), which will be housed in the animal facility untilthey reach seven months of age, a time point at which they already exhibit the typicalAD histopathology in this model. At this stage, we will administer PLX3397, aselective CSF1R inhibitor with high brain penetration, aiming to deplete microglia inthese animals. We expect that, following microglial depletion, the animals will showreduced inflammation and AD-related histopathology, as assessed byimmunohistochemistry for ¿-amyloid. We also anticipate improved cognitive function,evaluated through behavioral tests. Additionally, we will assess neuronal loss anddendritic spine density using Golgi staining.