Lipid droplets in neurodegenerative disorders: Molecular insights and therapeutic intervention

Lipid droplets (LDs) are dynamic lipid storage organelles, derived from phospholipid monolayer membrane of the endoplasmic reticulum. LDs are composed of neutral lipids, mainly including triglycerides, sterol esters, and other non-polar lipids like cholesterol. The functions of LDs differ from different cell types in the central nervous system. The major role of LDs is to maintain lipid homeostasis, provide energy supply, and play a protective role in response to intracellular oxidative stress in the brain. Oxidative stress can lead to lipid dyshomeostasis, particularly the accumulation of LDs, followed by abnormal myelination, neuroinflammation, and cognitive decline. Neuroinflammation, aging, and age-related neurodegenerative disorders (NDDs) are characterized by the excessive accumulation of LDs in the brain. Although the LDs accumulation in the brain of the NDDs mouse model has been reported as early as a century ago, the role of LDs in the brain remains largely unknown. It is still unclear regarding the involvement of LDs accumulation in the pathogenesis of NDDs. In this review, we provide an overview of LDs biogenesis, the characteristics and functions of LDs from a cell-type perspective, and the pathological roles of LDs in NDDs on recent advances. In addition, we discuss the emerging LDs-based therapeutic strategies for NDDs, which may provide promising clues to develop novel therapeutic approaches for NDDs.