Regulation of microglial metabolism and the implication in the inflammatory response of astrocytes during Alzheimer's disease

• Grant number: 21/10477-5
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): November 24, 2021
• Effective date (End): November 23, 2022
• Field of knowledge: Biological Sciences - Immunology
• Principal researcher: Thiago Mattar Cunha
• Grantee: Rafaela Mano Guimarães
• Supervisor abroad: Marco Collona
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: Washington University in St. Louis, United States
• Associated to the scholarship: 19/13829-0 - Role of O-GlcNAcylation in the neuroinflammatory functions of astrocytes, BP.DR

Abstract

Microglia and astrocytes are the most extensively studied cells beyond neurons in the CNS and are in a dynamic communication in healthy and diseased brains. Chronic neuroinflammation can cause synaptic dysfunction and neuronal death, being a common feature of neurodegenerative diseases, such as Alzheimer's disease (AD). In the past years, it has become evident that metabolism regulates the pathological inflammatory responses of microglia and astrocytes. Under resting conditions, microglia tend to be mainly dependent on oxidative phosphorylation for ATP production, while upon activation, they favor glycolysis, which results in increased glucose consumption and lactate production. In the AD context, a correlation between microglia-specific AD risk allele of TREM2 and metabolic function has been recently described: specifically, dysfunctional autophagy and mTOR signaling have been found in TREM2-deficient microglia. Despite the growing interest in this area, the specific contribution of glycolysis to microglial responses has not been fully defined yet. Here, we aim to investigate the participation of the LDHA enzyme to microglia functions and its implication in the inflammatory response of astrocytes during AD development. This enzyme catalyzes the conversion of pyruvate into lactate and helps to maintain nicotinamide adenine dinucleotide (NAD+) levels in the cell, sustaining glycolysis when the oxygen supply is restricted. In addition, lactate can be further used as an important energy source, gluconeogenic precursor, and signaling molecule. Understanding the metabolic signatures of different brain cells, and their metabolic interactions, will not only advance our understanding of how the brain functions and adapts to environmental demands, but may also elucidate the propensity of the brain to age-related neurodegenerative disorders. (AU)