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Peer-reviewedCC BYNature Neuroscience

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

  • Edoardo Moretto1,2,3
  • Anna Masato4,5
  • Chiara Panzi4,5
  • André T. Lopes4,5
  • Skye Stuart4,5
  • Samantha De La‐Rocque4,5
  • Maria Giuseppa Caso6
  • Ian J. White7
  • Sam Harris5
  • Marc Aurel Busche8,5,9
  • Giampietro Schiavo10,11
11 affiliations
  1. 1Department of Neuromuscular Diseases, UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK. [email protected]
  2. 2Institute of Neuroscience, CNR, Milan, Italy. [email protected]
  3. 3UK Dementia Research Institute at University College London, London, UK. [email protected]
  4. 4Department of Neuromuscular Diseases, UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK
  5. 5UK Dementia Research Institute at University College London, London, UK
  6. 6Institute of Neuroscience, CNR, Milan, Italy
  7. 7Laboratory for Molecular Cell Biology, University College London, London, UK
  8. 8Department of Biomedicine, University of Basel, Basel, Switzerland
  9. 9University Hospital of Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland
  10. 10Department of Neuromuscular Diseases, UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK. [email protected]
  11. 11UK Dementia Research Institute at University College London, London, UK. [email protected]
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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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Cite

BibTeXRIS
BibTeX
@article{moretto2026aberrant,
  title = {{Aberrant tau accumulation caused by MAPT mutations induces early pathological changes in axonal transport that are rescued by p38α inhibition}},
  author = {Edoardo Moretto and Anna Masato and Chiara Panzi and André T. Lopes and Skye Stuart and Samantha De La‐Rocque and Maria Giuseppa Caso and Ian J. White and Sam Harris and Marc Aurel Busche and Giampietro Schiavo},
  journal = {Nature Neuroscience},
  year = {2026},
  month = jun,
  doi = {10.1038/s41593-026-02266-4},
  url = {https://doi.org/10.1038/s41593-026-02266-4},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Aberrant tau accumulation caused by MAPT mutations induces early pathological changes in axonal transport that are rescued by p38α inhibition
AU  - Edoardo Moretto
AU  - Anna Masato
AU  - Chiara Panzi
AU  - André T. Lopes
AU  - Skye Stuart
AU  - Samantha De La‐Rocque
AU  - Maria Giuseppa Caso
AU  - Ian J. White
AU  - Sam Harris
AU  - Marc Aurel Busche
AU  - Giampietro Schiavo
PY  - 2026
DA  - 2026/06/01
JO  - Nature Neuroscience
DO  - 10.1038/s41593-026-02266-4
UR  - https://doi.org/10.1038/s41593-026-02266-4
AB  - 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.
SN  - 1097-6256
SN  - 1546-1726
ER  -