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

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

Alzheimer’s disease (AD) is a common debilitating age-related neurodegenerative condition characterized by progressive cognitive decline and pre-symptomatic accumulation of amyloid-β. Over 14 million people in Europe are living with dementia (60-70% AD diagnosis), which is projected to double by 2050. Currently, there is no treatment for AD; however, the dementia research community has made progress in characterizing the clinical and pathologic features of the disease and identifying risk factors. Indeed, 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. Upon activation, as a means to coordinate the immune response, the lipid organization of microglial cellular membranes is reorganized. To sustain this dynamic lipid remodeling, the cell coordinates a network of lipid pathways at unique subcellular regions, called MAMs (Mitochondria-associated ER membranes). The primary objective of the INFLAMAM project is to elucidate the mechanisms through which MAMs regulate microglial activation and to understand the consequences of MAM and lipid homeostasis defects in the context of AD. To achieve this, the project will integrate advanced lipidomics and proteomics techniques with both pharmacological and genetic interventions targeting MAMs. This comprehensive approach aims to identify key molecular drivers that mediate the interaction between lipid metabolism and immune signaling at MAMs in microglia. By establishing the role of MAMs as crucial hubs for immunometabolic regulation and drivers of AD pathogenesis, the INFLAMAM project aspires to identify new lipid pathways that could serve as targets for pharmacological interventions. These interventions could potentially mitigate the symptoms related to microglial activity in AD, offering new avenues for therapeutic development.

Data: CORDIS, © European Union