Disruption of sphingolipid metabolism promotes tau seeding through endolysosomal membrane rigidification and rupture

Alzheimer's disease and related tauopathies are characterized by endolysosomal dysfunction, although the precise mechanisms remain elusive. This research explores the role of sphingolipid metabolism in preserving endolysosomal membrane stability and its influence on tau aggregation and toxicity in model organisms, namely the roundworm Caenorhabditis elegans and human cell cultures.

Using techniques such as fluorescence recovery after photobleaching and C-Laurdan dye imaging, the findings indicate that silencing genes responsible for sphingolipid metabolism leads to a decrease in endolysosomal vesicle membrane fluidity, resulting in an increased likelihood of rupture. The buildup of aggregated tau within these endolysosomal compartments exacerbates the overall rigidity and damage to the endomembrane system, potentially facilitating the escape of tau seeds, which could contribute to the seeding of tau aggregation.

Supplementing the cell models with unsaturated fatty acids effectively improved membrane fluidity, mitigating endolysosomal rupture and the formation of tau seeds, and ultimately alleviated tau-linked neurotoxicity in the C. elegans model. Collectively, these findings offer a deeper understanding of how alterations in sphingolipid metabolism can promote endolysosomal membrane damage and facilitate the escape of aggregated tau, thereby highlighting the potential of restoring membrane fluidity as a therapeutic strategy to curb tau propagation and toxicity.