Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases
Soyoung Sung1, Hui-Ju Kim1, Sun Joo Cha2
1Department of Pharmacology, Research Institute of Basic Medical Science, School of Medicine, CHA University, CHA BIO COMPLEX, Seongnam-si, Gyeonggi-do, Republic of Korea.
Abstract:
Monoclonal antibodies approved for Alzheimer's disease (AD), such as lecanemab and aducanumab, have been shown to enhance microglial phagocytic function, underscoring the therapeutic relevance of microglia in neurodegenerative diseases (NDDs). Emerging evidence implicates lipid droplets (LDs) in brain aging and NDDs, particularly through LDs-laden microglia known as lipid droplet-accumulating microglia (LDAM), which exhibit impaired phagocytosis, elevated oxidative stress, and dysregulated lipid metabolism. Among microglial subtypes identified through transcriptomic and functional profiling-including disease-associated microglia (DAM), microglia in neurodegenerative disease (MGnD), white matter-associated microglia (WAM), and dark microglia-LDs-laden microglia have clear metabolic signatures defined by excessive LDs accumulation and disrupted lipid turnover. Here, we discuss the biogenesis of LDs, their pathological accumulation in microglia, and the therapeutic potential of targeting LDs. We further propose a hypothetical mechanism by which LDs clearance restore energy metabolism, nuclear transport, facilitate DNA repair, suppress inflammation, and phagocytosis in microglia. Thus, elucidating LDs dynamics in microglia may provide novel therapeutic avenues for modifying the course of NDDs.
Insights
Lipid droplets (LDs) in microglia are linked to neurodegenerative diseases (NDDs). Clearing these LDs may restore microglial function and offer new therapeutic strategies for brain aging and NDDs.
Area of Science:
- Neurobiology
- Cellular Metabolism
- Neuroinflammation
Background:
- Microglia, the brain's immune cells, are crucial in neurodegenerative diseases (NDDs).
- Recent Alzheimer's disease (AD) therapies target microglial function, highlighting their therapeutic relevance.
- Lipid droplets (LDs) and LDs-laden microglia (LDAM) are implicated in brain aging and NDDs, showing impaired functions.
Purpose of the Study:
- To discuss the biogenesis and pathological accumulation of LDs in microglia.
- To explore the therapeutic potential of targeting LDs in NDDs.
- To propose a mechanism for LD clearance restoring microglial functions.
Main Methods:
- Literature review on LD biogenesis and microglial subtypes.
- Analysis of transcriptomic and functional profiling data.
- Hypothetical mechanism proposal for LD clearance effects.
Main Results:
- LDs-laden microglia (LDAM) exhibit impaired phagocytosis, oxidative stress, and dysregulated lipid metabolism.
- LDAM possess distinct metabolic signatures characterized by excessive LD accumulation.
- LDs accumulation is linked to various microglial subtypes, including DAM, MGnD, WAM, and dark microglia.
Conclusions:
- Targeting LDs in microglia presents a novel therapeutic avenue for NDDs.
- LD clearance may restore microglial energy metabolism, DNA repair, and phagocytosis.
- Understanding LD dynamics in microglia is key to developing new NDD treatments.
