Lipid Droplet Remodeling at the Glia–Neuron Interface: Metabolic Sinks, Flux Traps, and Therapeutic Pitfalls in Neurodegeneration

Neurodegenerative diseases are characterized by progressive neurological decline, metabolic dysfunction, and chronic neuroinflammatory changes. Dysregulated lipid handling has emerged as an important component of these processes, but the functional significance of lipid droplets (LDs) remains strongly context-dependent. Here, we review LD biogenesis, turnover, and cell type-specific functions in the central nervous system (CNS) and critically evaluate evidence linking LD remodeling to neurodegeneration. Transient LD formation can buffer excess or oxidation-prone lipids and support metabolic adaptation, whereas persistent lipid retention in the setting of impaired lysosomal, mitochondrial, or lipid-export capacity is associated with cellular dysfunction. We compare human tissue data, genetic evidence, LD-specific perturbations, pharmacological studies, and experimental models across Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Particular attention is given to microglial lipid-associated states, neuron–glia lipid transfer, monogenic disorders of lipid handling, and apparently opposing outcomes of LD manipulation in different disease contexts. Rather than treating LD accumulation as a universal pathogenic mechanism, we propose LD remodeling as a candidate metabolic–inflammatory convergence state whose functional consequences depend on cell type, lipid composition, turnover capacity, and disease stage. Translational strategies should therefore prioritize direct measurements of LD flux, demonstration of CNS target engagement, and biomarker-guided patient and disease-stage selection. We further define experimental findings that would support or falsify the proposed convergence model.