Botulinum Neurotoxin Induces Neurotoxic Microglia Mediated by Exogenous Inflammatory Responses

Botulinum neurotoxin serotype A (BoNT/A) is widely used in therapeutics and cosmetics. The effects of multi‐dosed BoNT/A treatment are well documented on the peripheral nervous system (PNS), but much less is known on the central nervous system (CNS). Here, the mechanism of multi‐dosed BoNT/A leading...

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Bibliographic Details
Published in:Advanced science 2024-04, Vol.11 (15), p.e2305326-n/a
Main Authors: Ambrin, Ghuncha, Kang, You Jung, Van Do, Khanh, Lee, Charles, Singh, Bal Ram, Cho, Hansang
Format: Article
Language:English
Subjects:
Alzheimer's disease
Astrocytes
astrogliosis
Botulinum neurotoxin
Botulinum toxin
complement proteins
Cytokines
Gram-positive bacteria
human tri‐culture
Humans
microfluidics
Microglia - metabolism
Nervous system
Neurodegeneration
neuroinflammation
Neurons
proinflammatory microglia
Proteins
synaptic loss
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Summary:Botulinum neurotoxin serotype A (BoNT/A) is widely used in therapeutics and cosmetics. The effects of multi‐dosed BoNT/A treatment are well documented on the peripheral nervous system (PNS), but much less is known on the central nervous system (CNS). Here, the mechanism of multi‐dosed BoNT/A leading to CNS neurodegeneration is explored by using the 3D human neuron‐glia model. BoNT/A treatment reduces acetylcholine, triggers astrocytic transforming growth factor beta, and upregulates C1q, C3, and C5 expression, inducing microglial proinflammation. The disintegration of the neuronal microtubules is escorted by microglial nitric oxide, interleukin 1β, tumor necrosis factor α, and interleukin 8. The microglial proinflammation eventually causes synaptic impairment, phosphorylated tau (pTau) aggregation, and the loss of the BoNT/A‐treated neurons. Taking a more holistic approach, the model will allow to assess therapeutics for the CNS neurodegeneration under the prolonged use of BoNT/A. Microfluidic based humanized mini brain model is utilized to investigate the intoxication with BoNT/A at the CNS, mimicking clinical dosage treatments. Thsese results identifies astrocytes as the key regulator of complement proteins responding to reduced acetylcholine with BoNT/A treatment. Initial neuroinflammation by reactive astrocytes inducing microgliosis. The exacerbated response of the proinflammatory microglia results in synaptic impairment, oxidative stress and neurodegeneration.
ISSN:2198-3844
2198-3844
DOI:10.1002/advs.202305326