The complex web of membrane contact sites in brain aging and neurodegeneration

To sustain the essential biological functions required for life, eukaryotic cells rely on complex interactions between different intracellular compartments. Membrane contact sites (MCS), regions where organelles come into close proximity, have recently emerged as major hubs for cellular communication, mediating a broad range of physiological processes, including calcium signalling, lipid synthesis and bioenergetics. MCS are particularly abundant and indispensable in polarized and long-lived cells, such as neurons, where they support both structural and functional integrity. In this review, we explore the functional diversity, molecular composition, and dynamic regulation of key mammalian MCS: endoplasmic reticulum (ER)-plasma membrane, ER-mitochondria and contact sites involving lipid droplets. We highlight their central role in neuronal health and discuss how MCS dysfunction has increasingly been recognized as a hallmark of brain aging and various neurodegenerative diseases, most notably Alzheimer's disease, where altered MCS dynamics contribute to pathogenesis. Finally, we emphasize the therapeutic potential of targeting MCS and outline key unanswered questions to guide future research.