Detection of β-N-methylamino-l-alanine in postmortem olfactory bulbs of Alzheimer’s disease patients using UHPLC-MS/MS: An autopsy case-series study

Garamszegi, Susanna P.; Banack, Sandra Anne; Duque, Linda; Metcalf, James S.; Stommel, Elijah W.; Cox, Paul Alan; Da, Davis

doi:10.1016/j.toxrep.2023.01.002

Cited by 7 publications

(7 citation statements)

References 90 publications

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“…Outside of Guam, the BMAA toxin has been detected throughout the marine food web, including the brain and muscle tissues of apex predators [ 26 , 27 , 28 ]. BMAA has also been detected in autopsied brain samples and CSF of individuals with AD and ALS [ 29 , 30 , 31 ]. Thus, the presence of BMAA throughout the marine food web is a concern for apex predators and humans at risk of developing dementia and motor neuron disease.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the presence of BMAA throughout the marine food web is a concern for apex predators and humans at risk of developing dementia and motor neuron disease. Because the detection of BMAA in human tissue can vary due to a number of factors, examining marine mammals that have a lifetime risk of cyanotoxin exposure may provide more consistent measurements and allow for novel insights into BMAA’s mechanism of neurotoxicity [ 20 , 29 , 30 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

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TDP-43 and Alzheimer’s Disease Pathology in the Brain of a Harbor Porpoise Exposed to the Cyanobacterial Toxin BMAA

Garamszegi,

Brzostowicki,

Coyne

et al. 2024

Toxins

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Cetaceans are well-regarded as sentinels for toxin exposure. Emerging studies suggest that cetaceans can also develop neuropathological changes associated with neurodegenerative disease. The occurrence of neuropathology makes cetaceans an ideal species for examining the impact of marine toxins on the brain across the lifespan. Here, we describe TAR DNA-binding protein 43 (TDP-43) proteinopathy and Alzheimer’s disease (AD) neuropathological changes in a beached harbor porpoise (Phocoena phocoena) that was exposed to a toxin produced by cyanobacteria called β-N-methylamino-L-alanine (BMAA). We found pathogenic TDP-43 cytoplasmic inclusions in neurons throughout the cerebral cortex, midbrain and brainstem. P62/sequestosome-1, responsible for the autophagy of misfolded proteins, was observed in the amygdala, hippocampus and frontal cortex. Genes implicated in AD and TDP-43 neuropathology such as APP and TARDBP were expressed in the brain. AD neuropathological changes such as amyloid-β plaques, neurofibrillary tangles, granulovacuolar degeneration and Hirano bodies were present in the hippocampus. These findings further support the development of progressive neurodegenerative disease in cetaceans and a potential causative link to cyanobacterial toxins. Climate change, nutrient pollution and industrial waste are increasing the frequency of harmful cyanobacterial blooms. Cyanotoxins like BMAA that are associated with neurodegenerative disease pose an increasing public health risk.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TDP-43 and Alzheimer’s Disease Pathology in the Brain of a Harbor Porpoise Exposed to the Cyanobacterial Toxin BMAA

Garamszegi,

Brzostowicki,

Coyne

et al. 2024

Toxins

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“…153 The neurotoxin, β-methylamino-L-alanine, which was first associated with ALS and parkinsonism in Guam, 154 as well as fungal and bacterial infections, and certain intestinal disorders, have further been linked with increased AD risk. 144,155,156 Finally, military service is associated with AD pathology in post-mortem brain tissue. 157 Interestingly, interactions between lifestyle factors and known AD risk genes have been identified, particularly in apolipoprotein E 4ε (APOE ε4) carriers, which significantly influence an individual's response to their environment.…”

Section: The Neural Exposome and Admentioning

confidence: 99%

“…Both the intestinal and oral microbiome have been linked to AD risk, 148–152 and gut dysbiosis; that is, decreased protective Bacteroides , decreased butyrate‐producing bacteria, and increased inflammatory Prevotella , correlates with disease severity 153 . The neurotoxin, β‐methylamino‐L‐alanine, which was first associated with ALS and parkinsonism in Guam, 154 as well as fungal and bacterial infections, and certain intestinal disorders, have further been linked with increased AD risk 144,155,156 . Finally, military service is associated with AD pathology in post‐mortem brain tissue 157 …”

Section: The Neural Exposome and Admentioning

confidence: 99%

Role of the Exposome in Neurodegenerative Disease: Recent Insights and Future Directions

Sakowski,

Koubek,

Chen

et al. 2024

Annals of Neurology

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Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024

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“…The cyanobacterial neurotoxin BMAA can be directly transferred through olfactory pathways circumventing the BBB in mice and directly affecting olfactory neurons [ 260 ]. Recently, Garamszegi and co-authors [ 316 ] used triple quadrupole tandem mass spectrometry to demonstrate that BMAA and its isomers AEG and 2,4-DAB were detected in olfactory tissues of AD post-mortem brains. This finding contradicts early reports from Meneely and co-authors, who did not find BMAA in the brains of AD patients [ 124 ].…”

Section: Mechanisms Of Brain Toxicitymentioning

confidence: 99%

Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases

Nugumanova

Ponomarev

Askarova

et al. 2023

Toxins

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Cyanobacteria produce a wide range of structurally diverse cyanotoxins and bioactive cyanopeptides in freshwater, marine, and terrestrial ecosystems. The health significance of these metabolites, which include genotoxic- and neurotoxic agents, is confirmed by continued associations between the occurrence of animal and human acute toxic events and, in the long term, by associations between cyanobacteria and neurodegenerative diseases. Major mechanisms related to the neurotoxicity of cyanobacteria compounds include (1) blocking of key proteins and channels; (2) inhibition of essential enzymes in mammalian cells such as protein phosphatases and phosphoprotein phosphatases as well as new molecular targets such as toll-like receptors 4 and 8. One of the widely discussed implicated mechanisms includes a misincorporation of cyanobacterial non-proteogenic amino acids. Recent research provides evidence that non-proteinogenic amino acid BMAA produced by cyanobacteria have multiple effects on translation process and bypasses the proof-reading ability of the aminoacyl-tRNA-synthetase. Aberrant proteins generated by non-canonical translation may be a factor in neuronal death and neurodegeneration. We hypothesize that the production of cyanopeptides and non-canonical amino acids is a more general mechanism, leading to mistranslation, affecting protein homeostasis, and targeting mitochondria in eukaryotic cells. It can be evolutionarily ancient and initially developed to control phytoplankton communities during algal blooms. Outcompeting gut symbiotic microorganisms may lead to dysbiosis, increased gut permeability, a shift in blood-brain-barrier functionality, and eventually, mitochondrial dysfunction in high-energy demanding neurons. A better understanding of the interaction between cyanopeptides metabolism and the nervous system will be crucial to target or to prevent neurodegenerative diseases.

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Detection of β-N-methylamino-l-alanine in postmortem olfactory bulbs of Alzheimer’s disease patients using UHPLC-MS/MS: An autopsy case-series study

Cited by 7 publications

References 90 publications

TDP-43 and Alzheimer’s Disease Pathology in the Brain of a Harbor Porpoise Exposed to the Cyanobacterial Toxin BMAA

TDP-43 and Alzheimer’s Disease Pathology in the Brain of a Harbor Porpoise Exposed to the Cyanobacterial Toxin BMAA

Role of the Exposome in Neurodegenerative Disease: Recent Insights and Future Directions

Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases

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