BMAA is aderivative of the amino acidalanine with a methylamino group on theside chain. This non-proteinogenic amino acid is classified as apolar base.
BMAA is produced bycyanobacteria in marine, freshwater, and terrestrial environments.[2][3] In cultured non-nitrogen-fixing cyanobacteria, BMAA production increases in a nitrogen-depleted medium.[4] The biosynthetic pathway in cyanobacteria is unknown, but involvement of BMAA and its structural analog 2,4-diaminobutanoic acid (2,4-DAB) in environmental iron scavenging has been hypothesized.[5][6] BMAA has been found in aquatic organisms and in plants with cyanobacterialsymbionts such as certainlichens, the floating fernAzolla, the leafpetioles of the tropical flowering plantGunnera,cycads as well as in animals that eat the fleshy covering of cycad seeds, includingflying foxes.[7][8][9][10]
BMAA can cross theblood–brain barrier in rats. It takes longer to get into the brain than into other organs, but once there, it is trapped in proteins, forming a reservoir for slow release over time.[14][15]
Although the mechanisms by which BMAA causes motor neuron dysfunction and death are not entirely understood, current research suggests that there are multiple mechanisms of action. Acutely, BMAA can act as anexcitotoxin on glutamate receptors, such asNMDA, calcium-dependentAMPA, andkainate receptors.[16][17] The activation of themetabotropic glutamate receptor 5 is believed to induce oxidative stress in the neuron by depletion ofglutathione.[18]
A study performed in 2015 withvervet monkeys (Chlorocebus sabaeus) in St. Kitts, which are homozygous for theapoE4 gene (a condition which in humans is a risk factor for Alzheimer's disease), found that vervets that were administered BMAA orally developed hallmark histopathology features of Alzheimer's disease, includingamyloid beta plaques andneurofibrillary tangle accumulation. Vervets in the trial fed smaller doses of BMAA were found to have correlative decreases in these pathology features. Additionally, vervets that were co-administered BMAA withserine were found to have 70% less beta-amyloid plaques and neurofibrillary tangles than those administered BMAA alone, suggesting that serine may be protective against the neurotoxic effects of BMAA.
This experiment represents the first in-vivo model of Alzheimer's disease that features both beta-amyloid plaques and hyperphosphorylated tau protein. This study also demonstrates that BMAA, an environmental toxin, can trigger neurodegenerative disease as a result of a gene-environment interaction.[20]
Degenerative locomotor diseases have been described in animals grazing oncycad species, fueling interest in a possible link between the plant and theetiology of ALS/PDC. Subsequent laboratory investigations discovered the presence of BMAA. BMAA induced severe neurotoxicity inrhesus macaques, including:[21]
Scientists have also found that newborn rats treated with BMAA show a progressive neurodegeneration in the hippocampus, including intracellular fibrillar inclusions, and impaired learning and memory as adults.[23][24][25] BMAA has been reported to be excreted into rodent breast milk, and subsequently transferred to the suckling offspring, suggesting mothers' and cows' milk might be other possible exposure routes.[26]
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Chronic dietary exposure to BMAA is now considered to be a cause of theamyotrophic lateral sclerosis/parkinsonism–dementia complex (ALS/PDC) that had an extremely high rate of incidence among theChamorro people ofGuam.[27] The Chamorro call the conditionlytico-bodig.[28] In the 1950s, ALS/PDC prevalence ratios and death rates for Chamorro residents of Guam andRota were 50–100 times that of developed countries, including the United States.[28] No demonstrableheritable orviral factors were found for the disease, and a subsequent decline of ALS/PDC after 1963 on Guam led to the search for responsible environmental agents.[29] The use of flour made from cycad seed (Cycas micronesica[30]) in traditional food items decreased as that plant became rarer and the Chamorro population became more Americanized following World War II.[31] Cycads harbor symbioticcyanobacteria of the genusNostoc in specialized roots which push up through the leaf litter into the light; these cyanobacteria produce BMAA.[32]
In addition to eating traditional food items from cycad flour directly, BMAA may be ingested by humans throughbiomagnification.Flying foxes, a Chamorrodelicacy, forage on thefleshy seed covering of cycad seeds and concentrate the toxin in their bodies. Twenty-four specimens of flying foxes from museum collections were tested for BMAA, which was found in large concentrations in the flying foxes from Guam.[33] As of 2021 studies continued examining BMAA biomagnification in marine and estuarine systems and its possible impact on human health outside of Guam.[34]
Studies on human brain tissue of ALS/PDC, ALS,Alzheimer's disease, Parkinson's disease,Huntington's disease, and neurological controls indicated that BMAA is present in non-genetic progressive neurodegenerative disease, but not in controls or genetic-based Huntington's disease.[35][36][37][38]
As of 2021[update] research into the role of BMAA as an environmental factor in neurodegenerative disease continued.[39][40][41]
Safe and effective ways of treating ALS patients withL-serine that has been found to protect non-human primates from BMAA-induced neurodegeneration, have been goals of clinical trials conducted by the Phoenix Neurological Associates and the Forbes/Norris ALS/MND clinic and sponsored by the Institute for Ethnomedicine.[42][43]
^Esterhuizen M, Downing TG (2008). "β-N-methylamino-L-alanine (BMAA) in novel South African cyanobacterial isolates".Ecotoxicology and Environmental Safety.71 (2):309–313.doi:10.1016/j.ecoenv.2008.04.010.PMID18538391.
^Downing S, Banack SA, Metcalf JS, Cox PA, Downing TG (2011). "Nitrogen starvation of cyanobacteria results in the production of β-N-methylamino-L-alanine".Toxicon.58 (2):187–194.doi:10.1016/j.toxicon.2011.05.017.PMID21704054.
^Vega, A; Bell, A. (1967). "a-amino-β-methylaminopropionic acid, a new amino acid from seeds of cycas circinalis".Phytochemistry.6 (5):759–762.doi:10.1016/s0031-9422(00)86018-5.
^Field NC, Metcalf JS, Caller TA, Banack SA, Cox PA, Stommel EW (2013). "Linking β-methylamino-L-alanine exposure to sporadic amyotrophic lateral sclerosis in Annapolis, MD".Toxicon.70:179–183.doi:10.1016/j.toxicon.2013.04.010.PMID23660330.
^Spencer, Peter S.; Hugon, J.; Ludolph, A.; Nunn, P. B.; Ross, S. M.; Roy, D. N.; Schaumburg, H. H. (28 September 2007). "14: Discovery and Partial Characterization of Primate Motor-System Toxins". In Bock, Gregory; O'Connor, Maeve (eds.).Ciba Foundation Symposium 126 - Selective Neuronal Death. Novartis Foundation Symposia. Vol. 126. Wiley Online Library. pp. 221–238.doi:10.1002/9780470513422.ch14.ISBN978-0-470-51342-2.ISSN1935-4657.PMID3107939.
^Karlsson, O. (2011). Distribution and Long-term Effects of the Environmental Neurotoxin β-N-methylamino-L-alanine (BMAA): Brain changes and behavioral impairments following developmental exposure.http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-140785
^Galasko D, Salmon DP, Craig UK, Thal LJ, Schellenberg G, Wiederholt W (2002). "Clinical features and changing patterns of neurodegenerative disorders on Guam, 1997-2000".Neurology.58 (1):90–7.doi:10.1212/wnl.58.1.90.PMID11781411.S2CID24248686.
^Hill, K.D. (1994). "The cycas rumphii complex (Cycadeceae) in New Guinea and the Western Pacific".Australian Systematic Botany.7 (6):543–567.doi:10.1071/sb9940543.
^Banack SA, Murch SJ, Cox PA (2006). "Neurotoxic flying foxes as dietary items for the Chamorro people, Mariana Islands".Ethnopharmacology.106 (1):97–104.doi:10.1016/j.jep.2005.12.032.PMID16457975.
^Bradley, WG; Mash, DC (2009). "Beyond Guam: the cyanobacterial/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases".Amyotrophic Lateral Sclerosis.10:7–20.doi:10.3109/17482960903286009.PMID19929726.S2CID41622254.
