RT Journal Article
SR Electronic
T1 Microtubule assembly by soluble tau impairs vesicle endocytosis and excitatory neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.13.460074
DO 10.1101/2021.09.13.460074
A1 Hori, Tetsuya
A1 Eguchi, Kohgaku
A1 Wang, Han-Ying
A1 Miyasaka, Tomohiro
A1 Guillaud, Laurent
A1 Taoufiq, Zacharie
A1 Yamada, Hiroshi
A1 Takei, Kohji
A1 Takahashi, Tomoyuki
YR 2021
UL http://biorxiv.org/content/early/2021/09/14/2021.09.13.460074.abstract
AB 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 brainstem slices. 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 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.Significance Statement Wild-type human recombinant tau loaded in rodent presynaptic terminals inhibited vesicle endocytosis, thereby causing activity-dependent rundown of excitatory transmission. This endocytic block is caused by a sequestration of dynamin by excess microtubules newly assembled by tau and can be rescued by a peptide inhibiting the microtubules-dynamin interaction, or by the microtubule disassembler nocodazole. Thus, synaptic dysfunction can be induced by pathological increase of endogenous soluble tau in Alzheimer disease slice model.Competing Interest StatementThe authors have declared no competing interest.