Microtubule assembly by soluble tau impairs vesicle endocytosis and excitatory neurotransmission via dynamin sequestration in Alzheimer's disease mice synapse model
Elevation of soluble wild-type (WT) tau occurs in synaptic compartments in Alzheimer's disease. We addressed whether tau elevation affects synaptic transmission at the calyx of Held in slices from mice brainstem. Whole-cell loading of WT human tau (h-tau) in presynaptic terminals at 10-20 µM caused microtubule (MT) assembly and activity-dependent rundown of excitatory neurotransmission. Capacitance measurements revealed that the primary target of WT h-tau is vesicle endocytosis. Blocking MT assembly using nocodazole prevented tau-induced impairments of endocytosis and neurotransmission. Immunofluorescence imaging analyses revealed that MT assembly by WT h-tau loading was associated with an increased MT-bound fraction of the endocytic protein dynamin. A synthetic dodecapeptide corresponding to dynamin-1-pleckstrin-homology domain inhibited MT-dynamin interaction and rescued tau-induced impairments of endocytosis and neurotransmission. We conclude that elevation of presynaptic WT tau induces de novo assembly of MTs, thereby sequestering free dynamins. As a result, endocytosis and subsequent vesicle replenishment are impaired, causing activity-dependent rundown of neurotransmission.
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for All Figures.
Article and author information
Okinawa Institute of Science and Technology Graduate University
- Tomoyuki Takahashi
Core Research for Evolutional Science and Technology
- Tomoyuki Takahashi
Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research on Innovative Areas,26117004)
- Tomohiro Miyasaka
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All experiments were performed in accordance with the guidelines of the Physiological Society of Japan and animal experiment regulations at Okinawa Institute of Science and Technology Graduate University.
- Nils Brose, Max Planck Institute of Experimental Medicine, Germany
- Received: September 2, 2021
- Preprint posted: September 14, 2021 (view preprint)
- Accepted: April 20, 2022
- Accepted Manuscript published: April 26, 2022 (version 1)
- Version of Record published: May 5, 2022 (version 2)
© 2022, Hori et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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