Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons

Chiara Panzi; Sunaina Surana; Samantha De La-Rocque; Edoardo Moretto; Oscar Marcelo Lazo; Giampietro Schiavo

doi:10.1016/j.toxicon.2023.107110

Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons

Toxicon. 2023 Jun 1:228:107110. doi: 10.1016/j.toxicon.2023.107110. Epub 2023 Apr 8.

Authors

Chiara Panzi¹, Sunaina Surana², Samantha De La-Rocque³, Edoardo Moretto⁴, Oscar Marcelo Lazo², Giampietro Schiavo⁵

Affiliations

¹ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute, University College London, London, UK; UCL Queen Square Motor Neuron Disease Centre, University College London, London, UK. Electronic address: c.panzi@ucl.ac.uk.
² Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute, University College London, London, UK; UCL Queen Square Motor Neuron Disease Centre, University College London, London, UK.
³ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute, University College London, London, UK.
⁴ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute, University College London, London, UK; Institute of Neuroscience, CNR, 20854, Vedano al Lambro, Italy.
⁵ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute, University College London, London, UK; UCL Queen Square Motor Neuron Disease Centre, University College London, London, UK. Electronic address: giampietro.schiavo@ucl.ac.uk.

Abstract

Pathological tau aggregates propagate across functionally connected neuronal networks in human neurodegenerative pathologies, such as Alzheimer's disease. However, the mechanism underlying this process is poorly understood. Several studies have showed that tau release is dependent on neuronal activity and that pathological tau is found in the extracellular space in free form, as well as in the lumen of extracellular vesicles. We recently showed that metabotropic glutamate receptor activity and SNAP25 integrity modulate the release of pathological tau from human and mouse synaptosomes. Here, we have leveraged botulinum neurotoxins (BoNTs), which impair neurotransmitter release by cleaving specific synaptic SNARE proteins, to dissect molecular mechanisms related to tau release at synapses. In particular, we have tested the effect of botulinum neurotoxin A (BoNT/A) on the synaptic release of tau in primary mouse neurons. Hippocampal neurons were grown in microfluidic chambers and transduced with lentiviruses expressing human tau (hTau). We found that neuronal stimulation significantly increases the release of mutant hTau, whereas wild-type hTau is unaffected. Importantly, BoNT/A blocks mutant hTau release, indicating that this process is controlled by SNAP25, a component of the SNARE complex, in intact neurons. These results suggest that BoNTs are potent tools to study the spreading of pathological proteins in neurodegenerative diseases and could play a central role in identifying novel molecular targets for the development of therapeutic interventions to treat tauopathies.

Keywords: Alzheimer's disease; BoNT/A; Secretion; Spreading; Tau; Tauopathies.

MeSH terms

Animals
Botulinum Toxins, Type A* / pharmacology
Hippocampus / pathology
Humans
Mice
Neurons
Synaptic Transmission
Tauopathies* / metabolism
Tauopathies* / pathology

Substances

Botulinum Toxins, Type A