Microtubule assembly by soluble tau impairs vesicle endocytosis and excitatory neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model
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 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.
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Evaluation Summary:
Aggregates of the protein Tau are a key pathological features of Alzheimer's Disease and several other neurodegenerative disorders (Tauopathies). Hori et al. examined the effects of an acute elevation of Tau levels in synapses, employing high-end paired pre-post-synaptic patch-clamp recordings at the Calyx of Held model synapse. The authors generated a technically very rigorous dataset indicating that increased levels of soluble Tau impair pre-synaptic endocytosis and, consequently, neurotransmission by sequestering Dynamin-1 on microtubules, and propose that this process is part of a synaptic manifestation of Tauopathies. The findings are of major relevance for basic neuronal cell biology and translational neuroscience alike. However, several aspects of the proposed molecular mechanism underlying the synaptic …
Evaluation Summary:
Aggregates of the protein Tau are a key pathological features of Alzheimer's Disease and several other neurodegenerative disorders (Tauopathies). Hori et al. examined the effects of an acute elevation of Tau levels in synapses, employing high-end paired pre-post-synaptic patch-clamp recordings at the Calyx of Held model synapse. The authors generated a technically very rigorous dataset indicating that increased levels of soluble Tau impair pre-synaptic endocytosis and, consequently, neurotransmission by sequestering Dynamin-1 on microtubules, and propose that this process is part of a synaptic manifestation of Tauopathies. The findings are of major relevance for basic neuronal cell biology and translational neuroscience alike. However, several aspects of the proposed molecular mechanism underlying the synaptic effects of elevated Tau levels remain less clear.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Joint Public Review:
Aggregates of the protein Tau are key pathological features of Alzheimer's Disease and several other neurodegenerative disorders (Tauopathies). Hori et al. assessed the consequences of acute elevation of soluble Tau protein levels on pre-synaptic function using the Calyx of Held as an experimental model. The experimental approach is highly complex and technically challenging, particularly the direct pre-synaptic recordings with peptide infusion. Based on paired pre-post-synaptic recordings and pre-synaptic peptide infusion, the authors demonstrate that elevated Tau levels inhibit action-potential-evoked synaptic transmission, and pre-synaptic capacitance measurements show that Tau perturbs endocytosis but not pre-synaptic calcium currents, indicating that the depression of exocytic vesicle fusion is primarily a …
Joint Public Review:
Aggregates of the protein Tau are key pathological features of Alzheimer's Disease and several other neurodegenerative disorders (Tauopathies). Hori et al. assessed the consequences of acute elevation of soluble Tau protein levels on pre-synaptic function using the Calyx of Held as an experimental model. The experimental approach is highly complex and technically challenging, particularly the direct pre-synaptic recordings with peptide infusion. Based on paired pre-post-synaptic recordings and pre-synaptic peptide infusion, the authors demonstrate that elevated Tau levels inhibit action-potential-evoked synaptic transmission, and pre-synaptic capacitance measurements show that Tau perturbs endocytosis but not pre-synaptic calcium currents, indicating that the depression of exocytic vesicle fusion is primarily a consequence of inhibition of compensatory endocytosis. Further pharmacological perturbation experiments indicate that the effects of elevated Tau levels are likely caused by excessive microtubule polymerization or stability. Finally, evidence is provided, based on co-injection of high concentrations of a peptide derived from the lipid-binding PH domain of Dynamin-1, that Tau-induced microtubule stabilization may cause Dynamin-1 sequestration via direct microtubule binding. On aggregate, the data presented in this study support a model according to which soluble Tau impairs pre-synaptic endocytosis and neurotransmission in Alzheimer's Disease and related disorders by sequestering Dynamin-1 on microtubules.
Key Strength of the Paper
The experiments involved extremely difficult but highly informative patch-clamp electrophysiology techniques in combination with quantitative measurements to generate a highly rigorous data set.
Key Weakness of the Paper
The molecular and pharmacological perturbation experiments designed to elucidate the mechanism by which elevated Tau levels causes pre-synaptic defects are interesting and informative, but they not yet sufficient to support the firm conclusion that Tau-induced microtubule stabilization and the consequent Dynamin-1 sequestration via direct microtubule binding is at the basis of the Tau-induced synaptic defect.
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