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  1. 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.)

  2. 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.