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

• Published in: Toxicon (Oxford) 2023-06, Vol.228, p.107110-107110, Article 107110
• Main Authors: Panzi, Chiara, Surana, Sunaina, De La-Rocque, Samantha, Moretto, Edoardo, Lazo, Oscar Marcelo, Schiavo, Giampietro
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Alzheimer's disease; Animals; BoNT/A; botulinum toxin; Botulinum Toxins, Type A - pharmacology; extracellular space; glutamate receptors; Hippocampus - pathology; Humans; Lentivirus; Mice; mutants; Neurons; neurotransmitters; Secretion; Spreading; Synaptic Transmission; synaptosomes; Tau; Tauopathies; Tauopathies - metabolism; Tauopathies - pathology; therapeutics
• ISSN: 0041-0101; 1879-3150
• DOI: 10.1016/j.toxicon.2023.107110

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. •The release of pathologic tau is modulated by neuronal activity and components of the SNARE complex in hippocampal neurons.•Botulinum neurotoxins are potent tools to study the spreading of pathological proteins in the nervous system.•Botulinum neurotoxins may play a central role in identifying novel molecular targets for new treatments for tauopathies.