INFLAMAM · Role of Mitochondria-Associated ER membranes on microglia activation: implications for Alzheimer's disease.

Alzheimer’s disease (AD) is an irreversible neurodegenerative condition affecting 50 million people worldwide. Despite intense research, the pathological mechanisms of AD are still unclear. Many genetic loci robustly associated with AD code for proteins that are preferentially or exclusively expressed in microglia, supporting a causal role of microglia as key players in disease initiation and progression. Microglia are brain-resident immune cells that, upon activation, reorganize their cellular membranes by coordinating a network of lipid pathways at unique subcellular regions localized in the endoplasmic reticulum, called MAMs (Mitochondria-associated ER membranes), the membrane contact site between ER and mitochondria. Hyperactivation of MAM is shown to be associated with AD pathogenesis, however, the impact of MAM alteration on microglia biology is unexplored. The main objective of INFLAMAM is to determine the mechanism by which MAM regulates microglia activation, and the impact of defects in MAM and lipid homeostasis in the context of AD. To that aim, we propose to combine cutting-edge lipidomics and proteomics approaches with pharmacological and genetic MAM intervention strategies to identify relevant molecular drivers that enable the crosstalk between lipid metabolism and immune signaling at MAM in microglia. By proving the role of MAM as an immunometabolic hub for inflammation and a driver of AD pathogenesis, we believe this innovative project has the potential to pinpoint relevant lipid pathways as new targets for pharmacological intervention to alleviate the symptomatology related to microglia in AD.