Abstract
β-Methylamino-l-alanine (BMAA) is implicated in neurodegeneration and neurotoxicity, particularly in ALS-Parkinson Dementia Complex. Neurotoxic properties of BMAA have been partly elucidated, while its transcellular spreading capacity has not been examined. Using reconstructed neuronal networks in microfluidic chips, separating neuronal cells into two subcompartments—(1) the proximal, containing first-order neuronal soma and dendrites, and (2) a distal compartment, containing either only axons originating from first-order neurons or second-order striatal neurons—creates a cortico-striatal network. Using this system, we investigated the toxicity and spreading of BMAA in murine primary neurons. We used a newly developed antibody to detect BMAA in cells. After treatment with 10 μM BMAA, the cyanotoxin was incorporated in first-degree neurons. We also observed a rapid trans-neuronal spread of BMAA to unexposed second-degree neurons in 48 h, followed by axonal degeneration, with limited somatic death. This in vitro study demonstrates BMAA axonal toxicity at sublethal concentrations and, for the first time, the transcellular spreading abilities of BMAA. This neuronal dying forward spread that could possibly be associated with progression of some neurodegenerative diseases especially amyotrophic lateral sclerosis.
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Acknowledgements
VXT was funded by Macquarie University Research Excellence Scholarship and Post Graduate Research Funds, as well as a Campus France Eiffel Excellence Scholarship. GJG is funded by the Australian Research Council, Deb Bailey Foundation, MND and Me Foundation and Macquarie University. JMP is funded by ERANET Neuron 2012. The authors thank Dr. Pauline Vaur and Mr. Maxime Pennisson for their expert assistance in microdissection and Mr. Lucas Guillemin for producing Fig. 7.
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VXT, JMP and GJG formulated research ideas. VXT conducted the experiments. VXT, BL, PT and JC contributed to data analyses. Statistical analysis was undertaken by CKL and VXT. VXT, JMP, GJG, CKL and AB contributed to writing of paper.
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Animal ethics was approved by the C2EA-05 Comité d’éthique en expérimentation animale Charles Darwin.
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AB is the founder and CEO of ImmuSmol and provided the BMAA antibody and StainPerfect Kit.
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Gilles J. Guillemin and Jean-Michel Peyrin are co-last authors.
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Tan, V.X., Lassus, B., Lim, C.K. et al. Neurotoxicity of the Cyanotoxin BMAA Through Axonal Degeneration and Intercellular Spreading. Neurotox Res 33, 62–75 (2018). https://doi.org/10.1007/s12640-017-9790-1
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DOI: https://doi.org/10.1007/s12640-017-9790-1