Sphingolipid imbalance aggravates tau pathology by endomembrane rigidification and rupture

Endolysosomal dysfunction is a hallmark of Alzheimer’s disease (AD) and related tauopathies, yet underlying mechanisms remain poorly understood. This study investigates the role of sphingolipid metabolism in maintaining endolysosomal membrane integrity and its impact on tau aggregation and toxicity inCaenorhabditis elegansand human cell culture models. Fluorescence recovery after photobleaching and C-Laurdan dye imaging revealed that silencing sphingolipid metabolism genes reduced endolysosomal vesicle membrane fluidity, increasing their rupture. The accumulation of aggregated tau in endolysosomal vesicles further aggravated endomembrane rigidification and damage and promoted seeded tau aggregation, potentially by facilitating the escape of tau seeds from the endolysosomal system. Supplementation with unsaturated fatty acids improved membrane fluidity, suppressing endolysosomal rupture and seeded tau aggregation in cell models, and alleviating tau-associated neurotoxicity inC. elegans. This study provides mechanistic insights into how impaired sphingolipid homeostasis drives endolysosomal membrane damage and contributes to the progression of tau pathology, suggesting that restoring membrane fluidity may offer a therapeutic strategy for AD.