The cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) targets the olfactory bulb region

Abstract

Olfactory dysfunction is implicated in neurodegenerative disorders and typically manifests years before other symptoms. The cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) is suggested as a risk factor for neurodegenerative disease. Detection of BMAA in air filters has increased the concern that aerosolization may lead to human BMAA exposure through the air. The aim of this study was to determine if BMAA targets the olfactory system. Autoradiographic imaging showed a distinct localization of radioactivity in the right olfactory mucosa and bulb following a unilateral intranasal instillation of 3H-BMAA (0.018 µg) in mice, demonstrating a direct transfer of BMAA via the olfactory pathways to the brain circumventing the blood–brain barrier, which was confirmed by liquid scintillation. Treatment of mouse primary olfactory bulb cells with 100 µM BMAA for 24 h caused a disruption of the neurite network, formation of dendritic varicosities and reduced cell viability. The NMDA receptor antagonist MK-801 and the metabotropic glutamate receptor antagonist MCPG protected against the BMAA-induced alterations, demonstrating the importance of glutamatergic mechanisms. The ionotropic non-NMDA receptor antagonist CNQX prevented the BMAA-induced decrease of cell viability in mixed cultures containing both neuronal and glial cells, but not in cultures with neurons only, suggesting a role of neuron–glial interactions and glial AMPA receptors in the BMAA-induced toxicity. The results show that the olfactory region may be a target for BMAA following inhalation exposure. Further studies on the relations between environmental olfactory toxicants and neurodegenerative disorders are warranted.

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

“…Although this field is vast, one area of interest involves the naturally occurring bacterial toxin ß-N-methylamino-L-alanine (BMAA). Occasionally found in dangerously toxic concentrations within certain seafood, BMAA consumption has been shown to cause a significant shift in the microbial environment of the gut [ 122 , 123 ], demonstrating to have profound effects on the propagation of αSyn from the gut to the brain and the subsequent development of PD [ 122 , 124 ]. Interestingly, BMAA has causal links to both ALS and PD, being the key contributor to the rare incidence of the ALS-PD complex in the western Pacific islands of Guam and Japan [ 125 , 126 ].…”

Detection of β-N-methylamino-l-alanine in postmortem olfactory bulbs of Alzheimer’s disease patients using UHPLC-MS/MS: An autopsy case-series study

“…While the toxic effects of BMAA have been primarily reported via ingestion, emerging studies suggest that inhalation exposure may also provide risks for neurological illness [26] , [27] , [28] . This hypothesis is supported by animal models showing that intranasal administration of BMAA can transfer directly to and concentrate in the olfactory bulb ( Ob ) [29] . Direct application of the toxin to olfactory cells causes cell cycle arrest, excitotoxicity, reduced viability with cell death, and decreased mitochondrial function [29] , [30] , [31] , [32] .…”

“…This hypothesis is supported by animal models showing that intranasal administration of BMAA can transfer directly to and concentrate in the olfactory bulb ( Ob ) [29] . Direct application of the toxin to olfactory cells causes cell cycle arrest, excitotoxicity, reduced viability with cell death, and decreased mitochondrial function [29] , [30] , [31] , [32] . However, studies regarding BMAA exposures involving the human respiratory tract are still emerging [14] .…”

Is Exposure to BMAA a Risk Factor for Neurodegenerative Diseases? A Response to a Critical Review of the BMAA Hypothesis

“…Chernoff et al (2017) argue that previous studies do not facilitate determination of environmental BMAA concentrations that are dangerous to human health. The oral route is likely the primary way of BMAA exposure although recent studies have revealed that BMAA also can be transferred to the brain via the olfactory pathways (Pierozan et al 2020).…”

“…Misincorporation of BMAA is only one of many mechanisms acknowledged as possibly contributing to triggering sporadic neurodegenerative diseases (Chiu et al 2011;Arif et al 2014) and for examples since 2017 see (Beri et al 2017;Metcalf et al 2017;D'Mello et al 2017;Potjewyd et al 2017;Powers et al 2017;Engskog et al 2017;Michaelson et al 2017;Díaz-Parra et al 2017;Tan et al 2018a, b;Downing 2018, 2019;Albano and Lobner 2018;Main and Rodgers 2018;Laugeray et al 2018;Lepoutre et al 2018;Pierozan et al 2018Pierozan et al , 2020Gerić et al 2019;Cheng et al 2019;Pierozan and Karlsson 2019;Tedeschi et al 2019;Diaz-parga et al 2020;Li et al 2020;Ndaru et al 2020;Vallerga et al 2020). Chernoff et al (2017) presents multiple lines of evidence to refute that L-BMAA is a substrate for protein incorporation and we address these below.…”