alexa The Potential Role of BMAA in Neurodegeneration: Amyotrophic Lateral Sclerosis, Alzheimer’s Disease and Parkinsonism | Open Access Journals
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Journal of Alzheimers Disease & Parkinsonism
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The Potential Role of BMAA in Neurodegeneration: Amyotrophic Lateral Sclerosis, Alzheimer’s Disease and Parkinsonism

Tracie A Caller, Patricia L Henegan and Elijah W Stomme*

Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA

*Corresponding Author:
Elijah W Stommel
Department of Neurology
Geisel School of Medicine at Dartmouth
Hanover, NH 03755, USA
Tel: 603-650-8615

Received date: October 28, 2016; Accepted date: December 03, 2016; Published date: December 10, 2016

Citation: Caller TA, Henegan PL, Stommel EW (2016) The Potential Role of BMAA in Neurodegeneration: Amyotrophic Lateral Sclerosis, Alzheimer’s Disease and Parkinsonism. J Alzheimers Dis Parkinsonism 6:290. doi:10.4172/2161-0460.1000290

Copyright: ©2016 Caller TA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Neurodegenerative diseases are a major public health issue throughout the world with devastating effects on patients and families alike. Sporadic forms of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis are generally thought to develop as a consequence of genetic susceptibility and environmental influences. A number of environmental triggers have been identified in association with amyotrophic lateral sclerosis and Parkinson’s disease. We discuss the role of β-methylamino L-alanine in the development of neurodegeneration and the potential importance of this neurotoxin as a risk for neurodegeneration.


Amyotrophic lateral sclerosis; Alzheimer’s disease; Parkinson’s disease; β-methylamino L-alanine; Neurodegeneration

Neurodegenerative diseases are a collection of progressive, often fatal diseases that affect different parts of the nervous system and include amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and dementias such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). These diseases share a commonality of protein aggregate accumulation which leads to cellular dysfunction and eventually progressive neuronal death [1]. While familial variations of these disorders exist, the majority of cases occur sporadically, yet significant resources continue to be devoted to further studies of genetic etiologies and predispositions. For instance, in ALS, about 10-15% of cases are familial and transmitted genetically, and another small subset of cases result from sporadic mutations [2]. It is accepted that most likely an environmental exposure, and likely multiple environment insults, contribute to the development of disease. In ALS, a progressive disease of motor neurons that behaves much like cancer in its pattern of spread and rapidity of progression, it is postulated that as many as six insults (environmental with or without genetic susceptibility) are needed to produce clinical ALS [3].

The epidemiologic literature has postulated a number of possible environmental exposures related to ALS. A recent meta-analysis suggested lead, other heavy metals, farming exposure, and head injury as having suggestive evidence as risk factors, while weaker evidence was seen for electromagnetic fields and pesticides [4]. Other exposures including tobacco use, chemical and solvent exposure, and military service have conflicting findings [5-8]. In AD, there is strong evidence supporting increased risk associated with exposure to pesticides, tobacco use, and head trauma, while weaker evidence exists for aluminium, electromagnetic fields, and alcohol consumption [9]. Similarly, pesticides and farming increase the risk of PD, as do consumption of well water, rural dwelling, welding and manganese exposure; tobacco appears to be protective [10,11].

Investigation as to which environmental factors are of most concern is fraught with technical difficulties incurred by the large number of exposures a person may have in a lifetime and a significant lag time between exposure to risk factors and development of clinical signs of disease; preclinical forms of neurodegenerative diseases likely evolve over years before clinical symptoms become significant enough to warrant medical attention. In addition, there may be synergy of multiple toxins acting on the nervous system, similar to the observation that tobacco and radon exposure independently both increase the risk for lung cancer, but the risk is much higher when the two exposures occur concurrently.

β-methylamino L-alanine (BMAA), a neurotoxin produced by cyanobacteria, has been hypothesized to cause ALS and possibly other neurodegenerative diseases. Dietary consumption of BMAA became a concern during the investigation of an extraordinarily high rate of ALS and Parkinson’s Dementia Complex (PDC) that occurred in Guam and two other Western Pacific populations in the early-mid 20th century. An association between ALS and the consumption of cycad seeds was identified; cycad seeds contain cycasin (methylazoxymethanol-β-dglucoside), which is both neurotoxic and carcinogenic, and the neurotoxic nonprotein amino acid BMAA [12,13]. Cycad seeds were used by the natives to make tortilla flour, and in the process some of the BMAA was removed. BMAA in protein-bound form, however, could biomagnify up the food chain in animals such as flying foxes who fed on the same cycad seed, consequently delivering a large dose of BMAA to Chamorros who consumed these animals [14]. BMAA was subsequently identified in the brain tissue of Guam ALS patients [15]. The extinction of both the cycad seeds and the flying foxes, which were a delicacy in Guam, correlated with a substantial decline in the prevalence of neurodegenerative disease on the island [16,17]. The leading hypothesis remains exposure to an environmental toxin, with the notion that individuals exposed to higher doses of the toxin developed ALS-PDC at a relatively early age, and individuals exposed to a lesser dose developed dementia or other forms of neurodegeneration later in life [18]. An environmental cause would better account for the sharp decline in disease prevalence, increasing age of onset, and change in disease phenotype. The BMAA hypothesis in Guam generated concern among many scientists that chronic exposure to BMAA might increase the risk of ALS or other neurodegenerative diseases outside of Guam.

BMAA has been demonstrated by several independent studies to have the capability of crossing the blood brain barrier through an active transport mechanism [19,20]. BMAA is acutely neurotoxic via multiple mechanisms [21-23]. BMAA can bind to glutamate receptors, which mediate excitatory synaptic transmission; excessive binding could induce excitotoxicity where prolonged depolarization and changes in intracellular calcium concentrations activate cascades that results in cell death [22-25]. BMAA can also induce oxidative stress, another mechanism for which neurotoxicity can result [23,26,27]. Also of importance, BMAA may be present in isolation within an environment, or in combination with other cyanotoxins, heavy metals, or other environmental toxins which ultimately would impact the effect of exposure and subsequent development of neurodegeneration [28-31]. Lobner et al. demonstrated that BMAA at much lower concentrations, even as low as 10 μM, could potentiate neuronal injury induced by other toxins or insults with a synergistic effect such as when in the presence of mercury [32]. Early experiments using animal models demonstrated that large amounts of dietary BMAA were required to produce acute toxicity, whereas realistically, BMAA exposure through diet was likely at much lower concentrations. More recently, a mechanism of chronic toxicity has been postulated. BMAA may be incorporated into proteins by mischarging a tRNA (substituting for the amino acid L-serine), subsequently leading to protein misfolding, accumulation of protein aggregates, and apoptosis [33]. The incorporation of amino acid analogues into proteins has been previously demonstrated and could lead to cell dysfunction [34,35]. An example is the disease lathyrism, where a similar nonprotein amino acid (BOAA) acquired though chickpea consumption in the setting of malnutrition becomes neurotoxic [36]. Along similar lines, during WWII, the Chamorro natives of Guam were malnourished [37]; preexisting malnutrition and protein deficiency could result in the misincorporation of BMAA at a higher frequency, producing higher rates of disease or earlier onset of disease as was the case in the 1940s and 1950s [38].

Neuropathological studies have supported the link between BMAA and neurodegenerative diseases. Protein-bound BMAA has been detected in the brain tissue of Chamorro patients who died of ALS- PDC, but causation could not be assumed [15]. Spencer et al described pathological changes in macaques dosed with BMAA [39]; subsequent animal studies, predominantly using rodent models, were only able to identify acute toxicity [40]. To further explore the possibility of chronic exposure to BMAA as a cause of ALS-PDC on Guam, Cox et al fed BMAA injected fruit to vervet monkeys, using doses similar to what a typical Chamorro diet might have contained. Autopsy specimens of the vervet brains clearly demonstrated tissue loss as well as neurofibrillary tangles comprised of tau in the brains of the vervets that had been fed BMAA [41]. To our knowledge, this is the first animal model to demonstrate that dietary exposure to a toxin can produce pathological findings of a tauopathy (40). Although, the full methodology of tauopathy formations continues to be a question in the field, the direct cause is the hyperphosphorylation of the tau protein [42-44]. A few of the previous animal models that have been repeatedly used include: mice [45,46], rats [26,47,48], zebra fish [49], drosophila [50], and chickens [24].

The BMAA hypothesis may not be unique to Guam. Diverse taxa of ubiquitous cyanobacteria capable of producing BMAA are found in eutrophic freshwater and marine water bodies, and are an increasing environmental hazard in several parts of the world [51]. These toxin- producing cyanobacteria are often noticed when they form “blooms” on the surface of water bodies. The liver toxins such as microcystin produced by these blooms are a known health hazard, and associated with liver failure as well as hepatocellular carcinoma. The effects of acute exposure to BMAA through direct contact with blooms is unknown, and likely would require exposure to a substantial concentration to induce acute neurotoxic effects, but of greater concern is the effective chronic exposure to low levels of BMAA through inhalation, ingestion and direct contact. There is also potential for BMAA to accumulate in aquatic food chains, or through the use of cyanobacteria-contaminated water in irrigation of crops, resulting in human exposure outside of Guam [52-54]. Aerosolization of cyanobacteria can occur, and inhalation through wind or recreational sports such as water skiing may provide an additional route of chronic exposure to BMAA. BMAA has been detected in the brain tissue in patients from North America with ALS and sporadic AD, again supporting that exposure to BMAA outside of Guam is occurring [15,55]. Consequently, the increasing evidence incriminating BMAA as a potential trigger of neurodegeneration through chronic exposure has global ramifications.

Further work is needed to continue to explore the link between BMAA and other environmental toxins to development of neurodegenerative diseases. At present, there are no cures and available treatments are sparse, so identifying the preventable exposures that increase risk of neurodegenerative diseases is a critical step to reducing disease incidence. It is also hoped that by increasing our understanding of how these neurodegenerative diseases develop, that more effective treatment options may follow.


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