1. PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding.
- Author
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Soares AC, Ferreira A, Mariën J, Delay C, Lee E, Trojanowski JQ, Moechars D, Annaert W, and De Muynck L
- Subjects
- Animals, Hippocampus pathology, Mice, Mice, Inbred C57BL, Neurons pathology, Protein Transport, Tauopathies pathology, Hippocampus metabolism, Lysosomes metabolism, Neurons metabolism, Phosphatidylinositol 3-Kinases metabolism, Protein Aggregation, Pathological, Tauopathies metabolism, tau Proteins metabolism
- Abstract
Tauopathies, such as Alzheimer's disease (AD), are neurodegenerative disorders characterized by the deposition of hyperphosphorylated tau aggregates. Proteopathic tau seeds spread through the brain in a temporospatial pattern, indicative of transsynaptic propagation. It is hypothesized that reducing the uptake of tau seeds and subsequent induction of tau aggregation could be a potential approach for abrogating disease progression in AD. Here, we studied to what extent different endosomal routes play a role in the neuronal uptake of preformed tau seeds. Using pharmacological and genetic tools, we identified dynamin-1, actin, and Rac1 as key players. Furthermore, inhibition of PIKfyve, a protein downstream of Rac1, reduced both the trafficking of tau seeds into lysosomes and the induction of tau aggregation. Our work shows that tau aggregates are internalized by a specific endocytic mechanism and that their fate once internalized can be pharmacologically modulated to reduce tau seeding in neurons., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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