The seeding of tau pathology alters the endolysosomal system

Abstract

AbstractBackgroundTau pathology and endolysosomal alterations co‐occur in brains of Alzheimer’s Disease and other tauopathy patients, but the relationship between these two pathological features is currently not understood.MethodTau pathology can be modeled in vitro by seeding recombinant tau fibrils on human tau expressing cells, recapitulating tau hyperphosphorylation, misfolding and aggregation. The present study addressed how the seeding of tau pathology impacts the endolysosomal systemin various cell models. Cells expressing human GFP‐tau‐P301L were seeded with pre‐aggregated tau and fixed after 10 days for confocal and 3D‐STED analysis.ResultTau seeds were observed in early and late endosomal/lysosomal compartments. In iPSC‐derived human neurons, the seeding of tau pathology decreased the number, size and EEA1 labelling intensity of EEA1‐positive early endosomes. The effect on early endosomes was specific as the morphology of LAMP1‐positive late endosomes was not affected. Our data however did indicate a decreased proteolytic activity of these compartments suggesting that tau pathology seeding can causally affect endolysosomal function.ConclusionThe seeding of tau pathology can causally induce changes in the endolysosomal system, both on the morphological and the functional level. Such disturbances of this important recycling pathway in neurons may play a critical role in neurodegeneration observed in tauopathies.