β-N-Methylamino-L-Alanine is a developmental neurotoxin
- Authors: Scott, Laura Louise
- Date: 2019
- Subjects: Neurotoxic agents , Nervous system -- Diseases
- Language: English
- Type: Thesis , Doctoral , DPhil
- Identifier: http://hdl.handle.net/10948/43633 , vital:36949
- Description: β-N-methylamino-L-alanine (BMAA) has been implicated in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC), Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s Disease (AD), but to date no animal model has adequately substantiated this link at environmentally relevant or even exaggerated BMAA exposure levels. The resulting controversy over a possible role for BMAA in neurodegenerative diseases was further hampered by a lack of evidence for mechanistic explanation for the disease pathology associated with these diseases However, the different responses to BMAA that have been observed in neonatal compared to adult rats, together with the findings of epidemiological studies that exposure to environmental factors in utero or in the early stages of life may be important for the development of ALS several years later, suggested that age of exposure might be the determining factor of BMAA neurotoxicity. This study therefore specifically addresses the developmental nature of BMAA as a neurotoxin, and investigates the pathology and progressive nature of that pathology after exposure to the toxin at the most susceptible age. This study demonstrated the importance of BMAA exposure age over total BMAA dose by showing that the administration of a single neonatal dose of BMAA to rodents on postnatal day (PND) 3, 4 and 5, and not prenatally or on PND 6, 7 and 10, caused behavioural, locomotor, emotional and long-term cognitive deficits, clinical symptoms of neurodegeneration as well as pathological hallmarks of AD, PD and ALS in the central nervous system. Furthermore, the observed behavioural deficits and distribution of neuronal loss and proteinopathies in the rodent central nervous system following exposure to BMAA on PND 3, 4 and 5 (corresponding to the developing age of an infant during the third trimester of pregnancy) is consistent with that typically associated with the disruption of normal dopamine and/or serotonin signaling in the brain and the consequent alteration in normal hippocampal and striatal neurogenesis that is modulated, in part, by dopamine. The pattern of spread and rate of propagation of pathology in this neonatal rat BMAA model provided further evidence that BMAA potentially exerts its effect by acting on neurotransmitter signaling. The observed late onset of typical ALS symptoms and pathology suggest that in this BMAA model AD and/or PD related symptoms develop first, followed by the start of ALS symptoms only after the AD and/or PD neuropathological deficits have severely progressed. This study also demonstrated that BMAA exposure at different doses and at different developmental ages resulted in the development of different combinations of either AD and/or PD and/or ALS pathology and/or symptoms in rats, and it is therefore feasible that in humans the age and/or frequency of exposure as well as the BMAA dose might similarly be a major determinant of the variant of AD, PD and/or ALS that might develop in adulthood. Based on the low BMAA dose that was able to cause AD and/or PD-like neuropathological abnormalities in rats in this study, it is feasible that a pregnant human could over the course of her pregnancy, and specifically during the third trimester of pregnancy, consume sufficient BMAA to result in her unborn child developing AD and/or PD and/or ALS up to 30-50 years later. This neonatal BMAA model is the only non-transgenic rodent model that reproduces the behavioural deficits, neuropathology and clinical symptoms that are typically associated with AD, PD and ALS in humans and that, more importantly, mimics the delayed onset of disease symptoms and typical slow progression of these neurodegenerative diseases with age. It now seems very likely that BMAA is a developmental neurotoxin that, as a result of perinatal, but probably prenatal exposure, causes or contributes significantly to the development of neurodegenerative diseases in humans.
- Full Text:
- Date Issued: 2019
Potential for human exposure to Beta-N-methylamino-L-alanine in a freshwater system
- Authors: Scott, Laura Louise
- Date: 2014
- Subjects: Water quality biological assessment , Cyanobacteria , Neurotoxic agents
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/5159 , vital:20816
- Description: β-N-methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid associated with human neurodegenerative diseases. The content of BMAA in cyanobacteria is modulated by nitrogen in laboratory cultures. In order to evaluate the potential for human exposure, the nitrogen modulation of BMAA content needed verification in a natural environment. In accordance with laboratory culture studies, data presented in this study show that combined nitrogen was the most significant modulator of both cellular microcystin (MC) and BMAA content in phytoplankton in an environmental cyanobacterial bloom. While BMAA is produced upon nitrogen deprivation, MC is only produced at a specific nitrogen threshold where the rate of increase of nitrogen in the cell exceeds the carbon fixation rate. As BMAA and MC were detected in phytoplankton sourced from the Hartbeespoort Dam reservoir, the transfer of these cyanotoxins to organisms of higher trophic levels was investigated. Both BMAA and MC were detected at high concentrations in the liver and muscle tissue of fish sourced from the Hartbeespoort Dam reservoir indicating that consumption of fish from this reservoir constitutes a serious risk of exposure to cyanotoxins. In addition to the dietary exposure route to BMAA, two recent studies reported a correlation between Amyotrophic Lateral Sclerosis (ALS) incidence and the potential for aerosol exposure to cyanobacteria. With the absence of any evidence of the systemic distribution of BMAA following inhalation, an evaluation of the potential exposure risk associated with living in close proximity to this reservoir was deemed premature. A laboratory experiment investigating the effect and systemic fate of inhaled aerosolised BMAA was therefore conducted in order to determine the feasibility of inhalation as a potential BMAA exposure route. Data from the rat inhalation exposure study, however, showed that in rats BMAA inhalation may not constitute a significant mechanism of toxicity at environmental BMAA levels.
- Full Text:
- Date Issued: 2014