Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's disease.
ABSTRACT The aim of this study was to screen for and quantify the neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) in a cohort of autopsy specimens taken from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and non-neurological controls. BMAA is produced by cyanobacteria found in a variety of freshwater, marine, and terrestrial habitats. The possibility of geographically broad human exposure to BMAA had been suggested by the discovery of BMAA in brain tissues of Chamorro patients with ALS/Parkinsonism dementia complex from Guam and more recently in AD patients from North America. These observations warranted an independent study of possible BMAA exposures outside of the Guam ecosystem.
Postmortem brain specimens were taken from neuropathologically confirmed cases of 13 ALS, 12 AD, 8 HD patients, and 12 age-matched non-neurological controls. BMAA was quantified using a validated fluorescent HPLC method previously used to detect BMAA in patients from Guam. Tandem mass spectrometric (MS) analysis was carried out to confirm the identification of BMAA in neurological specimens.
We detected and quantified BMAA in neuroproteins from postmortem brain tissue of patients from the United States who died with sporadic AD and ALS but not HD. Incidental detections observed in two out of the 24 regions were analyzed from the controls. The concentrations of BMAA were below what had been reported previously in Chamarro ALS/ Parkinsonism dementia complex patients, but demonstrated a twofold range across disease and regional brain area comparisons. The presence of BMAA in these patients was confirmed by triple quadrupole liquid chromatography/mass spectrometry/mass spectrometry.
The occurrence of BMAA in North American ALS and AD patients suggests the possibility of a gene/environment interaction, with BMAA triggering neurodegeneration in vulnerable individuals.
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ABSTRACT: Cyanobacteria are a diverse group of ubiquitous environmental bacteria which can produce a wide array of toxins (cyanotoxins). While exposure to cyanotoxins from aquatic cyanobacterial blooms, scums and mats is a well-recognised cause of neurologic and hepatic disease in birds and animals , exposure of grazing livestock to terrestrial, as opposed to aquatic, cyanobacteria has not been previously described. We hypothesised that grazing livestock are exposed to Phormidium spp. since this cyanobacterial genus can grow on turf grasses and golf courses, particularly in favourable weather conditions and following fertiliser application -. Cyanobacteria including Phormidium spp. can produce a wide range of hepato-, neuro- and dermotoxins which cause disease in animals exposed to aquatic cyanobacterial blooms -. While exposure to anatoxin-a from the benthic cyanobacterium Phormidium favosum has been associated with canine neurotoxicosis , toxins from terrestrial Phormidium spp. have not been previously definitively associated with disease. We hypothesised that cyanotoxins from terrestrial Phormidium spp. may trigger or cause currently unexplained diseases of grazing livestock such as equine grass sickness (EGS), a frequently fatal multi-system neuropathy affecting grazing horses, equine motor neuron disease (EMND) and idiopathic hepatopathy. The aims of this study were to: (a) identify and enumerate Phormidium filaments in washings of the biofilm on plants collected from livestock-grazing fields; (b) evaluate spatial and temporal variation in the density of Phormidium filaments; (c) determine whether Phormidium filaments can be detected by microscopy in gastrointestinal contents from grazing horses; and (d) use a genomic approach to identify cyanobacteria in plant washings, equine ileal contents and soil. Additionally, a preliminary investigation of the potential association of cyanotoxins and EGS, EMND and hepatopathy was performed by: (a) comparing the density of Phormidium filaments on plants from horse fields immediately after an occurrence of EGS with that of plants from control horse fields; (b) quantifying the cyanobacterial neurotoxins 2,4-diaminobutyric acid [DAB], β-N-methylamino-L-alanine [BMAA] and N-(2-aminoethyl) glycine [AEG] in washings from plants collected from EGS fields; (c) quantifying DAB, BMAA and AEG in archived neural tissue from EGS and EMND horses; and (d) enumerating Phormidium spp. in washings of the biofilm on plants collected from fields grazed by horses which had idiopathic hepatopathy.Veterinary Research 02/2015; 46(16). DOI:10.1186/s13567-015-0143-x · 3.38 Impact Factor
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. It is typically fatal within 2–5 years of symptom onset. The incidence of ALS is largely uniform across most parts of the world, but an increasing ALS incidence during the last decades has been suggested. Although recent genetic studies have substantially improved our understanding of the causes of ALS, especially familial ALS, an important role of non-genetic factors in ALS is recognized and needs further study. In this review, we briefly discuss several major genetic contributors to ALS identified to date, followed by a more focused discussion on the most commonly examined non-genetic risk factors for ALS. We first review factors related to lifestyle choices, including smoking, intake of antioxidants, physical fitness, body mass index, and physical exercise, followed by factors related to occupational and environmental exposures, including electromagnetic fields, metals, pesticides, β-methylamino-L-alanine, and viral infection. Potential links between ALS and other medical conditions, including head trauma, metabolic diseases, cancer, and inflammatory diseases, are also discussed. Finally, we outline several future directions aiming to more efficiently examine the role of non-genetic risk factors in ALS.Clinical Epidemiology 02/2015; 7:181-193. DOI:10.2147/CLEP.S37505
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ABSTRACT: A cluster of amyotrophic lateral sclerosis (ALS) has been previously described to border Lake Mascoma in Enfield, NH, with an incidence of ALS approximating 25 times expected. We hypothesize a possible association with cyanobacterial blooms that can produce β-N-methylamino-L-alanine (BMAA), a neurotoxic amino acid implicated as a possible cause of ALS/PDC in Guam. Muscle, liver, and brain tissue samples from a Lake Mascoma carp, as well as filtered aerosol samples, were analyzed for microcystins (MC), free and protein-bound BMAA, and the BMAA isomers 2,4-diaminobutyric acid (DAB) and N-(2-aminoethyl)glycine (AEG). In carp brain, BMAA and DAB concentrations were 0.043 μg/g ± 0.02 SD and 0.01 μg/g ± 0.002 SD respectively. In carp liver and muscle, the BMAA concentrations were 1.28 μg/g and 1.27 μg/g respectively, and DAB was not OPEN ACCESS Toxins 2015, 7 323 detected. BMAA was detected in the air filters, as were the isomers DAB and AEG. These results demonstrate that a putative cause for ALS, BMAA, exists in an environment that has a documented cluster of ALS. Although cause and effect have not been demonstrated, our observations and measurements strengthen the association.Toxins 01/2015; 7(2):322-336. DOI:10.3390/toxins7020322 · 2.48 Impact Factor