Cyanobacterial neurotoxin BMAA in ALS and Alzheimer’s disease. Acta Neurol Scand

Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Acta Neurologica Scandinavica (Impact Factor: 2.4). 03/2009; 120(4):216-25. DOI: 10.1111/j.1600-0404.2008.01150.x
Source: PubMed


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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    • "BMAA is a developmental neurotoxicant that can induce long-term learning and memory deficits, as well as regionally restricted neuronal degeneration and mineralization in the hippocampal cA1. The aim of the study was to characterize long-term changes (2 weeks to 6 months) further in the brain of adult rats treated neonatally (postnatal days 9–10) with BMAA 2003; Pablo et al. 2009; spencer et al. 1987), and behavioral deficits have been demonstrated in rodents, monkeys, and insects exposed to BMAA (Karlsson et al. 2009c; Okle et al. 2013; spencer et al. 1987; Zhou et al. 2009). A recent in vitro study has suggested that BMAA can be misincorporated into proteins, which may result in the formation of protein aggregates in cultured cells (Dunlop et al. 2013). "
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    ABSTRACT: The environmental neurotoxin β-N-methylamino-l-alanine (BMAA) has been implicated in the etiology of neurodegenerative disease, and recent studies indicate that BMAA can be misincorporated into proteins. BMAA is a developmental neurotoxicant that can induce long-term learning and memory deficits, as well as regionally restricted neuronal degeneration and mineralization in the hippocampal CA1. The aim of the study was to characterize long-term changes (2 weeks to 6 months) further in the brain of adult rats treated neonatally (postnatal days 9-10) with BMAA (460 mg/kg) using immunohistochemistry (IHC), transmission electron microscopy, and laser capture microdissection followed by LC-MS/MS for proteomic analysis. The histological examination demonstrated progressive neurodegenerative changes, astrogliosis, microglial activation, and calcification in the hippocampal CA1 3-6 months after exposure. The IHC showed an increased staining for α-synuclein and ubiquitin in the area. The ultrastructural examination revealed intracellular deposition of abundant bundles of closely packed parallel fibrils in neurons, axons, and astrocytes of the CA1. Proteomic analysis of the affected site demonstrated an enrichment of chaperones (e.g., clusterin, GRP-78), cytoskeletal and intermediate filament proteins, and proteins involved in the antioxidant defense system. Several of the most enriched proteins (plectin, glial fibrillar acidic protein, vimentin, Hsp 27, and ubiquitin) are known to form complex astrocytic inclusions, so-called Rosenthal fibers, in the neurodegenerative disorder Alexander disease. In addition, TDP-43 and the negative regulator of autophagy, GLIPR-2, were exclusively detected. The present study demonstrates that neonatal exposure to BMAA may offer a novel model for the study of hippocampal fibril formation in vivo.
    Archives of Toxicology 05/2014; 89(3). DOI:10.1007/s00204-014-1262-2 · 5.98 Impact Factor
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    • "The examination of other ecosystems has demonstrated the presence of BMAA in fish and crustaceans in the human food chain in Florida, Chesapeake Bay, France and Sweden [15-18]. BMAA has been demonstrated to be concentrated in the brains of ALS patients (but not controls) in Florida [19] and to be mis-incorporated into neuronal proteins via the L-serine tRNA-synthetase system [20-22]. Clusters of ALS have been reported near cyanobacterial bloom outbreaks in France, Japan, New Hampshire, and Wisconsin [23-27]. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease with a lifetime risk of developing as 1 in 700. Despite many recent discoveries about the genetics of ALS, the etiology of sporadic ALS remains largely unknown with gene-environment interaction suspected as a driver. Water quality and the toxin beta methyl-amino-alanine produced by cyanobacteria are suspected environmental triggers. Our objective was to develop an eco-epidemiological modeling approach to characterize the spatial relationships between areas of higher than expected ALS incidence and lake water quality risk factors derived from satellite remote sensing as a surrogate marker of exposure. Our eco-epidemiological modeling approach began with implementing a spatial clustering analysis that was informed by local indicators of spatial autocorrelation to identify locations of normalized excess ALS counts at the census tract level across northern New England. Next, water quality data for all lakes over 6 hectares (n = 4,453) were generated using Landsat TM band ratio regression techniques calibrated with in situ lake sampling. Derived lake water quality risk maps included chlorophyll-a (Chl-a), Secchi depth (SD), and total nitrogen (TN). Finally, a spatially-aware logistic regression modeling approach was executed characterizing relationships between the derived lake water quality metrics and ALS hot spots. Several distinct ALS hot spots were identified across the region. Remotely sensed lake water quality indicators were successfully derived; adjusted R2 values ranged between 0.62-0.88 for these indicators based on out-of-sample validation. Map products derived from these indicators represent the first wall-to-wall metrics of lake water quality across the region. Logistic regression modeling of ALS case membership in localized hot spots across the region, i.e., census tracts with higher than expected ALS counts, showed the following: increasing average SD within a radius of 30 km corresponds with a decrease in the odds of belonging to an ALS hot spot by 59%; increasing average TN within a radius of 30 km and average Chl-a concentration within a radius of 10 km correspond with increased odds of belonging to an ALS hot spot by 167% and 4%, respectively. The strengths of satellite remote sensing information can help overcome traditional field limitations and spatiotemporal data gaps to provide the public health community valuable exposure data. Geographic scale needs to be diligently considered when evaluating relationships among ecological processes, risk factors, and human health outcomes. Broadly, we found that poorer lake water quality was significantly associated with increased odds of belonging to an ALS cluster in the region. These findings support the hypothesis that sporadic ALS (sALS) can, in part, be triggered by environmental water-quality indicators and lake conditions that promote harmful algal blooms.
    International Journal of Health Geographics 01/2014; 13(1):1. DOI:10.1186/1476-072X-13-1 · 2.62 Impact Factor
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    • "Although a large number of cyanotoxins are known for their rapid and acute toxicity, neurotoxic amino acids, shown to be produced by cyanobacteria, have gained interest due to their connection to long-term human neurodegenerative diseases (Cox et al., 2003; Murch et al., 2004). In particular, b-N-methylamino- L-alanine (BMAA) has been identified in 95% of cyanobacterial strains tested (Cox et al., 2005; Esterhuizen and Downing, 2008) and also occurs in the brains of patients who died of Amyotrophic Lateral Sclerosis (ALS), Alzheimer's and Parkinson's disease (Bradley and Mash, 2009; Murch et al., 2004; Pablo et al., 2009). A characteristic shared by all Gram-negative bacteria is their capacity to produce lipopolysaccharide (LPS; Drews and Weckesser, 1982). "
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    ABSTRACT: This article reviews current knowledge on cyanobacteria, the dominant primary producers, and other microorganisms in arid desert environments. These microorganisms have developed an array of adaptations to hot, arid climates with intense UV radiation, extreme diurnal temperature fluctuations, and high soil salinity. Crust microorganisms positively contribute to their harsh ecosystems, by preventing evapotranspiration, fixing nitrogen, and blocking solar radiation. In doing so, desert crust prevents soil erosion and facilitates the establishment of plant species. However, like aquatic cyanobacteria, desert cyanobacteria have the potential to produce toxins linked to human and animal illness. Furthermore, the impact of terrestrial cyanobacterial toxins on human health in desert regions is poorly understood. A largely ignored, but potentially important human exposure route for cyanotoxins in desert environments is through the inhalation of desert crusts during dust storms and anthropogenic activity. Future work in this field should include the characterization of toxins produced in desert regions as well as the presence of toxins in clinical and environmental materials.
    Journal of Arid Environments 12/2013; 112. DOI:10.1016/j.jaridenv.2013.11.004 · 1.64 Impact Factor
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