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Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons
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 a...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Pergamon Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10636589/ https://www.ncbi.nlm.nih.gov/pubmed/37037273 http://dx.doi.org/10.1016/j.toxicon.2023.107110 |
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author | Panzi, Chiara Surana, Sunaina De La-Rocque, Samantha Moretto, Edoardo Lazo, Oscar Marcelo Schiavo, Giampietro |
author_facet | Panzi, Chiara Surana, Sunaina De La-Rocque, Samantha Moretto, Edoardo Lazo, Oscar Marcelo Schiavo, Giampietro |
author_sort | Panzi, Chiara |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10636589 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Pergamon Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-106365892023-11-14 Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons Panzi, Chiara Surana, Sunaina De La-Rocque, Samantha Moretto, Edoardo Lazo, Oscar Marcelo Schiavo, Giampietro Toxicon Article 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. Pergamon Press 2023-06-01 /pmc/articles/PMC10636589/ /pubmed/37037273 http://dx.doi.org/10.1016/j.toxicon.2023.107110 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Panzi, Chiara Surana, Sunaina De La-Rocque, Samantha Moretto, Edoardo Lazo, Oscar Marcelo Schiavo, Giampietro Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons |
title | Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons |
title_full | Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons |
title_fullStr | Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons |
title_full_unstemmed | Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons |
title_short | Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons |
title_sort | botulinum neurotoxin a modulates the axonal release of pathological tau in hippocampal neurons |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10636589/ https://www.ncbi.nlm.nih.gov/pubmed/37037273 http://dx.doi.org/10.1016/j.toxicon.2023.107110 |
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