Role of microglia depletion in a genetic model of Alzheimer's Disease: neuroprotection or neurodegeneration?

• Grant number: 24/16877-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2025
• End date: June 30, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luiz Roberto Giorgetti de Britto
• Grantee: Beatriz Gangale Muratori
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Alzheimer's Disease (AD) is the most prevalent form of dementia. It is a progressive neurodegenerative disorder associated with aging in its sporadic form, primarily affecting women. AD is characterized by the presence of ¿-amyloid plaques (¿A) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, which are associated with neuronal death and inflammatory processes mediated by microglia and astrocytes. The role of microglia in AD is controversial, as it can contribute to both neurodegeneration and neuroprotection at different stages of the disease. This project aims to investigate the mechanisms of action of microglia and its participation in neurodegeneration and neuroprotection, contributing to a better understanding of AD. To achieve this, we will use triple-transgenic mice (3xTG-AD) and wild-type animals (C57BL/6) as controls. Microglial depletion will be performed using PLX3397, a CSF1R inhibitor that selectively depletes microglia by compromising their viability, and we will evaluate how prolonged microglial depletion affects the prevention, progression, or stabilization of AD, depending on the depletion timing and animal age. Animals will undergo behavioral tasks to assess memory, anxiety, and motor function. Additionally, we will perform analyses of pro- and anti-inflammatory cytokine expression, morphological characterization, and microglial activation, as well as evaluation of classical AD pathological features, such as tau and ¿-amyloid expression. Neuronal loss will be characterized by NeuN staining, cholinergic neurons, and somatostatin-secreting interneurons, as well as local synaptic activity through synapsin staining. (AU)