Tau seeding in neurons enabled by transient endolysosomal perforations are confined within endolysosomes.

ABSTRACT: Pathogenic tau assemblies propagate by templated seeding. For endocytosed fibrils to initiate aggregation of endogenous tau, a breach must occur in the limiting membrane of an endosome or lysosome. To study the route by which internalized tau seeds access cytosolic monomers and to identify the site of aggregate growth, we imaged live human iPSC-derived neurons (iNs) expressing tau P301L-eGFP after exposure to recombinant tau pre-formed fibrils (PFFs) or Alzheimer's disease (AD) brain-derived oligomers or fibrils. We detected seeded tau P301L-eGFP aggregation within late endosomes/lysosomes of iNs but not in undifferentiated iPSCs. Colocalization with a Dextran pH biosensor showed that the aggregates remained within the lumen of an intact, low-pH compartment. Reporters of endolysosomal inju

SUBMITTER: Sanyal A 

PROVIDER: S-EPMC12637672 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature