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Aberrant tau accumulation caused by MAPT mutations induces early pathological changes in axonal transport that are rescued by p38α inhibition

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Moretto, Edoardo, Masato, Anna, Panzi, Chiara, Lopes, André T., Stuart, Skye, De La-Rocque, Samantha, Caso, Maria Giuseppa, White, Ian J. +3 more·2026·Nature Neuroscience
DOI 10.1038/s41593-026-02266-4PMC PMC13246509
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Abstract

Impairments in axonal transport have been implicated in the pathogenesis of tauopathies, including frontotemporal dementia and Alzheimer’s disease, yet the underlying mechanisms and reversibility of these deficits are largely unknown. In particular, the impacts of tau mutations, phosphorylation and aggregation on axonal transport in vivo remain controversial. By using two-photon imaging of axonal transport of BDNF granules in the mouse cortex, we reveal that deficits in axonal transport arise in vivo at early stages of tau pathology, preceding tangle formation and neuronal death. Mechanistically, these impairments are caused by the enlargement of tau envelopes on microtubules, which act as functional barriers for transport. Crucially, these deficits are reversed by inhibiting MAPK p38α. Together, our work demonstrates that tau pathology causes reversible deficits in axonal transport in vivo, posing the basis for pharmacological interventions to restore the physiological flux of axonal organelles and cargoes in tauopathies.

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  • Prior to oligomerization and late-stage aggregation, hyperphosphorylated tau first impairs transport, which then contributes to axonal decline.

    “prior to oligomerization and late-stage aggregation, hyperphosphorylated tau first impairs transport, which then contributes to axonal decline”

    From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Moretto et al., 2026

    The Discussion (page not provided) reports transport deficits in mice with highly phosphorylated mutant tau before overt aggregation, and links tau phosphorylation to those deficits. It suggests that impaired transport contributes to neurodegeneration, but does not establish that it causes subsequent axonal decline or that the deficits precede oligomerization specifically. (LLM, conf=0.85)

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Authors
Moretto, E., Masato, A., Panzi, C., Lopes, A. T., Stuart, S., De La-Rocque, S., Caso, M. G., White, I. J., Harris, S. S., Busche, M. A., & Schiavo, G.
Affiliations
  • UK Dementia Research Institute (GB)
  • National Research Council (IT)
  • MRC Laboratory for Molecular Cell Biology (GB)
  • University of Basel (CH)
Corresponding author
  • Moretto, Edoardo
  • Schiavo, Giampietro
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2026-06
Volume
29
Issue
6
Pages
1355-1368
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-026-02266-4
PMC
PMC13246509
OpenAlex
W7163533330
Cited by
4
References
9
Citations by year
2026: 4
FWCI
15.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
tauopathy, axonal transport, MAPT mutations, tau phosphorylation, tau aggregation, frontotemporal dementia, Alzheimer's disease
MeSH terms
Alzheimer Disease, Animals, Axonal Transport, Brain, Doxycycline, Mice, Inbred C57BL, Microtubules, Neurons, Phosphorylation, tau Proteins, Cell Death, Brain-Derived Neurotrophic Factor, Mitogen-Activated Protein Kinase 11, Mitogen-Activated Protein Kinase 14, Mice, Frontotemporal Dementia, Neuroimaging

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