Mechanisms of oligodendrocyte dysfunction in Alzheimer's Disease

• Grant number: 24/18129-4
• Support Opportunities: Scholarships in Brazil - Program to Stimulate Scientific Vocations
• Start date: February 03, 2025
• End date: March 22, 2025
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Mychael Vinícius da Costa Lourenço
• Grantee: Thiago Ziggiatti Ucio Pompeo
• Host Institution: Instituto de Bioquímica Médica. Universidade Federal do Rio de Janeiro (UFRJ). Ministério da Educação (Brasil)

Abstract

Alzheimer's disease (AD) is characterized by cognitive decline and progressive neurodegeneration in specific brain regions. Although a prevalent hypothesis in the field suggests that amyloid plaques (formed by the beta-amyloid peptide) and neurofibrillary tangles (formed by the tau protein) cause neuronal toxicity and are considered the main pathological markers of the disease, very recent studies suggest that glial cells, such as oligodendrocytes, also play a critical role in AD progression. Oligodendrocytes are cells responsible for myelinating axons in the central nervous system, which is essential for the rapid conduction of nerve impulses. Furthermore, these cells appear to be crucial for lipid homeostasis in the brain. Dysfunction of these cells leads to demyelination and impairment of neural circuit integrity, which may contribute to the cognitive deficits observed in AD. Additionally, there is growing evidence that oligodendrocytes are vulnerable to the accumulation of toxic proteins, such as beta-amyloid and hyperphosphorylated tau, resulting in metabolic and signaling dysfunctions. This research project aims to investigate in detail the mechanisms leading to oligodendrocyte dysfunction in AD. To this end, in vitro studies will be conducted using oligodendrocyte cell lines exposed to conditions that mimic the neurodegenerative microenvironment of AD, such as soluble aggregates of beta-amyloid and tau. The main cellular signaling pathways involved in oligodendrocyte homeostasis, as well as global gene expression and cellular health markers, will be investigated. The processes identified in these experiments will then be investigated in the brains of animal models of AD and in postmortem samples from AD patients. Thus, the main goal of the project is to determine how alterations in oligodendrocyte homeostasis contribute to neurodegeneration in AD. This study may open new avenues for the development of innovative therapies focused on protecting brain function in AD patients. (AU)