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

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

doi:10.1016/j.toxicon.2023.107110

Cited by 3 publications

(3 citation statements)

References 80 publications

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“…To note, Chiara Panzi et al demonstrated that therapeutic BoNT reduces the release of mutant Tau protein, a causative agent of Alzheimer’s disease, in the primary mouse hippocampal neurons (Panzi et al 2023). Solabre Valois et al reported that the incubation of hippocampal neurons with a non-toxic C-terminal region of the receptor-binding domain of heavy chain BoNT promoted the axonal outgrowth of dendritic arborizations via the activation of small Ras-related C3 botulinum toxin substrate (Rac)-1 Rho guanosine triphosphate hydrolases (GTPases) and extracellular signal-regulated kinase (ERK) pathway (Solabre Valois et al 2021).…”

Section: Discussionmentioning

confidence: 99%

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The proneurogenic and microglial modulatory properties of botulinum toxin in the hippocampus of aging experimental mice

Joseph,

Babu Deva Irakkam,

Kandasamy

2024

Preprint

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This study explored the neurogenic and microglial modulatory properties of botulinum toxin in the hippocampus of aging experimental mice. Therapeutic botulinum toxin (BoNT) treatment is widely practiced to reduce the excessive discharge of acetylcholine (ACh) in the management of aging and neurological deficits. While the production of new neurons in the adult brain contributes to cognitive functions, age-related diseases with excessive release of ACh and progressive neuroinflammation have been characterized by impaired hippocampal neurogenesis and memory loss. Therefore, we investigated the effect of BoNT on the regulation of hippocampal neurogenesis, focusing on doublecortin (DCX)-positive immature neurons in the hippocampus of aging experimental mice. We also assessed ionized calcium-binding adapter molecule 1 (Iba1)-positive microglia and the expression of cyclooxygenase (COX)-2, a key inflammatory response element, using reverse transcription polymerase chain reaction (RT-PCR). Results revealed a prominent increase in DCX-positive cells in the BoNT-treated animals compared to the control group. Additionally, the reduced number of microglia accompanied by decreased mRNA expression of COX-2 was evident in the BoNT-treated animals. These dual effects suggest that BoNT could be a promising therapeutic agent for mitigating age-related neuroregenerative decline and neuroinflammation responsible for cognitive impairments.

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Section: Discussionmentioning

confidence: 99%

“…mutant Tau protein, a causative agent of Alzheimer's disease, in the primary mouse hippocampal neurons(Panzi et al 2023). Solabre Valois et al reported that the incubation of hippocampal neurons with a non-toxic C-terminal region of the receptor-binding domain of heavy chain…”

mentioning

confidence: 99%

The proneurogenic and microglial modulatory properties of botulinum toxin in the hippocampus of aging experimental mice

Joseph,

Babu Deva Irakkam,

Kandasamy

2024

Preprint

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“…Accordingly, in the context of a different neurodegenerative disorder (Alzheimer’s disease), it has been shown that tau release from rodent and human synaptosomes is a calcium- and SNAP-25-dependent mechanism sensitive to BoNT/A treatment. Indeed, the cleavage of SNAP-25 by BoNT/A modulates the release of pathologic tau [ 29 , 32 ]. Moreover, since the expression of SNARE fusion machinery has been largely assessed at the postsynaptic site, the delivery of BoNT/s has been exploited to better investigate AMPA and NMDA glutamate receptor insertion and diffusion during neuronal activity and plasticity.…”

Section: Introduction: General Features and Experimental Applications...mentioning

confidence: 99%

Action of Botulinum Neurotoxin E Type in Experimental Epilepsies

Antonucci,

Bozzi

2023

Toxins

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Botulinum neurotoxins (BoNTs) are zinc endopeptidases produced by the Clostridium genus of anerobic bacteria, largely known for their ability to cleave synaptic proteins, leading to neuromuscular paralysis. In the central nervous system, BoNTs are known to block the release of glutamate neurotransmitter, and for this reason, researchers explored the possible therapeutic action in disorders characterized by neuronal hyperactivity, such as epilepsy. Thus, using multidisciplinary approaches and models of experimental epilepsy, we investigated the pharmacological potential of BoNT/E serotype. In this review, written in memory of Prof. Matteo Caleo, a pioneer in these studies, we go back over the hypotheses and experimental approaches that led us to the conclusion that intrahippocampal administration of BoNT/E (i) displays anticonvulsant effects if prophylactically delivered in a model of acute generalized seizures; (ii) does not have any antiepileptogenic action after the induction of status epilepticus; (iii) reduces frequency of spontaneous seizures in a model of recurrent seizures if delivered during the chronic phase but in a transient manner. Indeed, the control on spontaneous seizures stops when BoNT/E effects are off (few days), thus limiting its pharmacological potential in humans.

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Synaptic Release of Pathological Tau Is Calcium- and SNAP25-Dependent, and Blocked by BoNT-A Activity

Masato,

Panzi,

Butnaru

et al. 2024

Toxicon

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

Cited by 3 publications

References 80 publications

The proneurogenic and microglial modulatory properties of botulinum toxin in the hippocampus of aging experimental mice

The proneurogenic and microglial modulatory properties of botulinum toxin in the hippocampus of aging experimental mice

Action of Botulinum Neurotoxin E Type in Experimental Epilepsies

Synaptic Release of Pathological Tau Is Calcium- and SNAP25-Dependent, and Blocked by BoNT-A Activity

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