Cuní-López Carla, Root Jessica T, Hao Ying, Kowal Isabelle, Blomberg Niek, Ghirlando Rodolfo, Yang Linda G, Koppes-den Hertog Sascha J, Cookson Mark R, van der Kant Rik, Giera Martin, Qi Yue Andy, Narayan Priyanka S
Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD USA.
Center for Alzheimer's and Related Dementias (CARD), National Institutes of Health, Bethesda, MD, USA.
bioRxiv. 2025 Aug 20:2025.08.19.669163. doi: 10.1101/2025.08.19.669163.
The lipids and proteins that comprise lipid droplets regulate several cellular functions including lipid storage, stress responses, and inflammation. Glial lipid droplets have been implicated in the pathogenesis and progression of Alzheimer's disease (AD), yet the mechanisms linking genetic risk to lipid droplet biology remain unclear. Here we examined how , the strongest genetic modulator of late-onset AD, impacts lipid droplet composition and dynamics. We defined the lipid droplet-associated proteome and lipidome in human induced pluripotent stem cell-derived astrocytes harboring the three common genotypes: (protective), (neutral), and (risk). Each variant displays distinct lipid droplet-associated proteins and lipids. These molecular changes yield differences in lipophagy; lipid droplets in astrocytes undergo autophagic turnover, whereas those in astrocytes are resistant to degradation. These findings suggest that impaired lipid droplet clearance, rather than accumulation, distinguishes -associated AD risk, and may present a new metabolic node for modulating risk.
构成脂滴的脂质和蛋白质调节多种细胞功能，包括脂质储存、应激反应和炎症。神经胶质脂滴与阿尔茨海默病（AD）的发病机制和进展有关，但将遗传风险与脂滴生物学联系起来的机制仍不清楚。在这里，我们研究了晚发性AD最强的遗传调节因子如何影响脂滴组成和动态。我们在携带三种常见基因型的人诱导多能干细胞衍生的星形胶质细胞中定义了脂滴相关蛋白质组和脂质组：（保护性）、（中性）和（风险）。每个变体都显示出不同的脂滴相关蛋白质和脂质。这些分子变化导致了脂质自噬的差异；星形胶质细胞中的脂滴经历自噬周转，而星形胶质细胞中的脂滴则抗降解。这些发现表明，脂滴清除受损而非积累是与相关AD风险的区别所在，并且可能呈现出一个调节风险的新代谢节点。
