Environmental neurotoxin interaction with proteins: Dose-dependent increase of free and protein-associated BMAA (β-N-methylamino-L-alanine) in neonatal rat brain.

Oskar Karlsson,Leopold L Ilag,Liying Jiang,Tim Malmström,Lisa Ersson,Eva B Brittebo

doi:10.1038/srep15570

Oskar Karlsson, Leopold L Ilag + Show 4 more

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https://doi.org/10.1038/srep15570

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Abstract

β-Methylamino-L-alanine (BMAA) is implicated in the aetiology of neurodegenerative disorders. Neonatal exposure to BMAA induces cognitive impairments and progressive neurodegenerative changes including intracellular fibril formation in the hippocampus of adult rats. It is unclear why the neonatal hippocampus is especially vulnerable and the critical cellular perturbations preceding BMAA-induced toxicity remains to be elucidated. The aim of this study was to compare the level of free and protein-associated BMAA in neonatal rat brain and peripheral tissues after different exposures to BMAA. Ultra-high performance liquid chromatography-tandem mass spectrometry analysis revealed that BMAA passed the neonatal blood-brain barrier and was distributed to all studied brain areas. BMAA was also associated to proteins in the brain, especially in the hippocampus. The level in the brain was, however, considerably lower compared to the liver that is not a target organ for BMAA. In contrast to the liver there was a significantly increased level of protein-association of BMAA in the hippocampus and other brain areas following repeated administration suggesting that the degradation of BMAA-associated proteins may be lower in neonatal brain than in the liver. Additional evidence is needed in support of a role for protein misincorporation in the neonatal hippocampus for long-term effects of BMAA.

Highlights

Our previous autoradiographic imaging studies of radiolabelled BMAA in adult and neonatal rodents revealed a tissue distribution pattern similar to protein-forming amino acids, indicating that BMAA may be incorporated or associated with newly synthesized proteins[22,23,24,25]
In the central nervous system the level of free BMAA was similar in all studied brain areas whereas the hypothalamus had a higher level
The cyanobacterial toxin BMAA has been implicated in the aetiology of neurodegenerative disorders[4,11,33] and the uptake and potential protein-association of BMAA in mammalian central nervous system are of concern[29,31,34]

Summary

Introduction

Our previous autoradiographic imaging studies of radiolabelled BMAA in adult and neonatal rodents revealed a tissue distribution pattern similar to protein-forming amino acids, indicating that BMAA may be incorporated or associated with newly synthesized proteins[22,23,24,25]. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis revealed a dose-dependent increase of protein-associated BMAA in the neonatal liver and to a lower extent in brain regions not fully protected by the blood-brain barrier[25]. No protein-association was detected in BMAA-exposed zooplankton grazer Daphnia magna free BMAA was detected in this species[32]. The aim of this study was to characterize the tissue distribution of free and protein-associated BMAA following various doses and exposures in neonatal rats using UHPLC-MS/MS with special reference to the BMAA-induced long-term damage in the adult hippocampus of neonatally exposed rats

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