A critical review of the postulated role of the non-essential amino acid, β-N-methylamino-L-alanine, in neurodegenerative disease in humans

Abstract

The compound BMAA (β-N-methylamino-L-alanine) has been postulated to play a significant role in four serious neurological human diseases: Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) found on Guam, and ALS, Parkinsonism, and dementia that occur globally. ALS/PDC with symptoms of all three diseases first came to the attention of the scientific community during and after World War II. It was initially associated with cycad flour used for food because BMAA is a product of symbiotic cycad root-dwelling cyanobacteria. Human consumption of flying foxes that fed on cycad seeds was later suggested as a source of BMAA on Guam and a cause of ALS/PDC. Subsequently, the hypothesis was expanded to include a causative role for BMAA in other neurodegenerative diseases including Alzheimer's disease (AD) through exposures attributed to proximity to freshwaters and/or consumption of seafood due to its purported production by most species of cyanobacteria. The hypothesis that BMAA is the critical factor in the genesis of these neurodegenerative diseases received considerable attention in the medical, scientific, and public arenas. This review examines the history of ALS/PDC and the BMAA-human disease hypotheses; similarities and differences between ALS/PDC and the other diseases with similar symptomologies; the relationship of ALS/PDC to other similar diseases, studies of BMAA-mediated effects in lab animals, inconsistencies and data gaps in the hypothesis; and other compounds and agents that were suggested as the cause of ALS/PDC on Guam. The review concludes that the hypothesis of a causal BMAA neurodegenerative disease relationship is not supported by existing data.

Occurrence of β-N-methylamino-l-alanine (BMAA) and Isomers in Aquatic Environments and Aquatic Food Sources for Humans

“…Some cases of high ALS incidence in various countries (e.g., Guam, United States, and France) have been linked to a possible long-term consumption of BMAA-contaminated food [ 41 , 43 , 44 ]. The implication of a potent BMAA biomagnification in the Guam terrestrial food web as a dietary factor causing ALS disease is still debated [ 45 ]. The presence of BMAA in primary producers and in organisms of higher trophic levels is reported, but there is no strong evidence of the BMAA trophic transfer.…”

Genotoxic and Cytotoxic Effects on the Immune Cells of the Freshwater Bivalve Dreissena polymorpha Exposed to the Environmental Neurotoxin BMAA

“…As bats were traditional food items on Guam, human contamination is thought to have occurred during the consumption of whole individuals [ 3 , 5 ]. However, this hypothesis is subject to controversy [ 6 ]. The BMAA toxic mechanism has not been fully determined, but current research shows that the neurotoxin may (i) form carbamate adducts when conjugated with bicarbonate ions at physiological concentrations, inducing a motoneuron excitotoxicity via the L-glutamate receptors [ 7 , 8 , 9 ], which can lead to an oxidative stress an cell death [ 8 , 9 ]; (ii) inhibit the synthesis and/or the stimulation of glutamine degradation [ 10 ]; (iii) inhibit cells cysteine/glutamate antiporter, leading to a depletion of glutathione (GSH) which increases oxidative stress [ 8 ]; and (iv) bind to or incorporate into proteins during their synthesis [ 11 ], although this hypothesis has been criticized [ 12 ].…”

Antineuroinflammatory Activities and Neurotoxicological Assessment of Curcumin Loaded Solid Lipid Nanoparticles on LPS-Stimulated BV-2 Microglia Cell Models

“…Neurodegenerative diseases, such as Parkinson’s disease (PD) or Alzheimer’s disease, are age-related chronic illnesses that are characterized by the loss of neurons and activation of microglia in brain cells [1,2]. Numerous studies have confirmed that neuroinflammation is a major factor of the degeneration in nigral neurons that are important characteristics of neurodegenerative diseases [3].…”