Microglial lipid metabolism: a delicate balance

Egmond, N. van (2025)

Doctoral Thesis

Microglia support the central and peripheral nervous system by forming the first line of defense against hazardous events. Microglia are increasingly acknowledged as critical players in neurodegenerative diseases, highlighting them as potential therapeutic targets. Microglia respond swiftly to external cues by adopting appropriate and unique phenotypes, known as microglial states. Microglial states were long conveyed as pro- versus anti-inflammatory, or M1 versus M2. This binary perspective on microglial states is increasingly challenged by the emergence of single-cell omics studies in neurodegenerative diseases. The discovery of highly specialized microglial states raises doubts about the feasibility of a ‘one-size-fits-all’ approach to medicine, where targeting ‘bad’ or ‘good’ microglia to impair or promote their functioning, respectively, might not be achievable. At the same time, the classification of drugs as either pro- or anti-inflammatory has become outdated, as their efficacy may vary depending on the microglial
state. This underscores the need for a better understanding of the mechanisms of action of drugs and the microglial state-dependent functions of proteins they target. The emerging role of lipid metabolism imbalances in neurodegenerative diseases underscores the importance of advancing our understanding into how lipids and lipid-metabolizing enzymes regulate microglial functioning. Microglia are increasingly recognized as critical, active contributors to the progression of neurodegeneration. Given the association between neurodegenerative diseases and dysfunctional lipid metabolism, this thesis aims to explore lipid metabolism in microglial biology, with a specific focus on lipid pathways identified as potentially suited for therapeutic intervention.

• Microglia
• Lipids
• Lipid metabolism
• Endocannabinoid system
• ABHD12
• Inflammation
• Neurodegeneration
• Myelin phagocytosis

• All authors: Egmond, N. van
• Supervisor: Stelt, M. van der; Kasteren, S.I. van
• Committee: Ubbink, M.; Aerts, J.M.F.G.; Spaink, H.P.; Bonger, K.M.; Huitinga, I.; Witte, L.D. de
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Institute of Chemistry (LIC), Faculty of Science, Leiden University
• Date: 2025-06-18
• ISBN (print): 9789465221403