Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer's disease synapse model

Hori T, Eguchi K, Wang HY, Miyasaka T, Guillaud L, Taoufiq Z, Mahapatra S, Yamada H, Takei K, Takahashi T. 2022. Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model. eLife. 11, e73542.

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Author
Hori, Tetsuya; Eguchi, KohgakuISTA ; Wang, Han Ying; Miyasaka, Tomohiro; Guillaud, Laurent; Taoufiq, Zacharie; Mahapatra, Satyajit; Yamada, Hiroshi; Takei, Kohji; Takahashi, Tomoyuki
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Abstract
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.
Publishing Year
Date Published
2022-05-05
Journal Title
eLife
Acknowledgement
We thank Yasuo Ihara, Nobuyuki Nukina, and Takeshi Sakaba for comments and Patrick Stoney for editing this paper. We also thank Shota Okuda and Mikako Matsubara for their contributions in the early stage of this study, and Satoko Wada-Kakuda for technical assistant with in vitro analysis of tau. This research was supported by funding from Okinawa Institute of Science and Technology and from Technology (OIST) and Core Research for the Evolutional Science and Technology of Japan Science and Technology Agency (CREST) to TT, and by Scientific Research on Innovative Areas to TM (Brain Protein Aging and Dementia Control 26117004).
Volume
11
Article Number
e73542
eISSN
IST-REx-ID

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Hori T, Eguchi K, Wang HY, et al. Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model. eLife. 2022;11. doi:10.7554/eLife.73542
Hori, T., Eguchi, K., Wang, H. Y., Miyasaka, T., Guillaud, L., Taoufiq, Z., … Takahashi, T. (2022). Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model. ELife. eLife Sciences Publications. https://doi.org/10.7554/eLife.73542
Hori, Tetsuya, Kohgaku Eguchi, Han Ying Wang, Tomohiro Miyasaka, Laurent Guillaud, Zacharie Taoufiq, Satyajit Mahapatra, Hiroshi Yamada, Kohji Takei, and Tomoyuki Takahashi. “Microtubule Assembly by Tau Impairs Endocytosis and Neurotransmission via Dynamin Sequestration in Alzheimer’s Disease Synapse Model.” ELife. eLife Sciences Publications, 2022. https://doi.org/10.7554/eLife.73542.
T. Hori et al., “Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model,” eLife, vol. 11. eLife Sciences Publications, 2022.
Hori T, Eguchi K, Wang HY, Miyasaka T, Guillaud L, Taoufiq Z, Mahapatra S, Yamada H, Takei K, Takahashi T. 2022. Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model. eLife. 11, e73542.
Hori, Tetsuya, et al. “Microtubule Assembly by Tau Impairs Endocytosis and Neurotransmission via Dynamin Sequestration in Alzheimer’s Disease Synapse Model.” ELife, vol. 11, e73542, eLife Sciences Publications, 2022, doi:10.7554/eLife.73542.
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