Botulinum Neurotoxin Induces Neurotoxic Microglia Mediated by Exogenous Inflammatory Responses

Area of Science:

• Neuroscience
• Toxicology
• Cell Biology

Background:

• Botulinum neurotoxin serotype A (BoNT/A) is extensively used therapeutically and cosmetically.
• While its peripheral nervous system (PNS) effects are known, its impact on the central nervous system (CNS) remains under-investigated.
• Understanding BoNT/A's CNS mechanisms is crucial due to its widespread application.

Purpose of the Study:

• To elucidate the mechanism by which multi-dosed BoNT/A induces neurodegeneration in the CNS.
• To investigate the cellular and molecular changes associated with prolonged BoNT/A exposure in a human 3D neuron-glia model.
• To provide a foundation for developing therapeutic strategies against BoNT/A-induced CNS damage.

Main Methods:

• Utilized a 3D human neuron-glia model to simulate CNS environments.
• Analyzed biochemical changes including acetylcholine levels and growth factor expression.
• Assessed inflammatory markers in microglia and neuronal structural integrity.

Main Results:

• BoNT/A treatment decreased acetylcholine and increased transforming growth factor beta in astrocytes.
• Upregulation of complement factors (C1q, C3, C5) and microglial pro-inflammatory mediators (NO, IL-1β, TNF-α, IL-8) was observed.
• Neuronal microtubule disintegration, synaptic impairment, phosphorylated tau (pTau) aggregation, and neuron loss were documented.

Conclusions:

• Multi-dosed BoNT/A triggers a cascade of neuroinflammatory events in the CNS.
• These events lead to synaptic dysfunction, tau pathology, and ultimately neuronal death.
• The 3D model offers a platform for evaluating potential treatments for BoNT/A-related CNS neurodegeneration.