BMAA can cross the
blood–brain barrier in rats. It takes longer to get into the brain than into other organs, but once there, it is trapped in proteins, forming a reservoir for slow release over time.
Mechanisms Although the mechanisms by which BMAA causes motor neuron dysfunction and death are not entirely understood, current research suggests that there are multiple mechanisms of action. Acutely, BMAA can act as an
excitotoxin on glutamate receptors, such as
NMDA, calcium-dependent
AMPA, and
kainate receptors. The activation of the
metabotropic glutamate receptor 5 is believed to induce oxidative stress in the neuron by depletion of
glutathione. BMAA can be misincorporated into nascent proteins in place of
-serine, possibly causing protein misfolding and aggregation, both hallmarks of
tangle diseases, including
Alzheimer's disease,
Parkinson's disease,
amyotrophic lateral sclerosis (ALS),
progressive supranuclear palsy (PSP), and
Lewy body disease.
In vitro research has shown that protein association of BMAA may be inhibited in the presence of excess -serine.
Effects A study performed in 2015 with
vervet monkeys (
Chlorocebus sabaeus) in St. Kitts, which are homozygous for the
apoE4 gene (a condition which in humans is a risk factor for Alzheimer's disease), found that vervets that were administered BMAA orally developed hallmark histopathology features of Alzheimer's disease, including
amyloid beta plaques and
neurofibrillary tangle accumulation. Vervets in the trial fed smaller doses of BMAA were found to have correlative decreases in these pathology features. Additionally, vervets that were co-administered BMAA with
serine were found to have 70% less beta-amyloid plaques and neurofibrillary tangles than those administered BMAA alone, suggesting that serine may be protective against the neurotoxic effects of BMAA. This experiment represents the first in-vivo model of Alzheimer's disease that features both beta-amyloid plaques and hyperphosphorylated tau protein. This study also demonstrates that BMAA, an environmental toxin, can trigger neurodegenerative disease as a result of a gene-environment interaction. Degenerative locomotor diseases have been described in animals grazing on
cycad species, fueling interest in a possible link between the plant and the
etiology of ALS/PDC. Subsequent laboratory investigations discovered the presence of BMAA. BMAA induced severe neurotoxicity in
rhesus macaques, including: • limb muscle
atrophy • nonreactive degeneration of
anterior horn cells • degeneration and partial loss of
pyramidal neurons of the
motor cortex • behavioral dysfunction •
conduction deficits in the central motor pathway • neuropathological changes of motor cortex
Betz cells There are reports that low BMAA concentrations can selectively kill
cultured motor neurons from mouse
spinal cords and produce
reactive oxygen species. Scientists have also found that newborn rats treated with BMAA show a progressive neurodegeneration in the hippocampus, including intracellular fibrillar inclusions, and impaired learning and memory as adults. BMAA has been reported to be excreted into rodent breast milk, and subsequently transferred to the suckling offspring, suggesting mothers' and cows' milk might be other possible exposure routes.
Human cases Chronic dietary exposure to BMAA is now considered to be a cause of the
amyotrophic lateral sclerosis/
parkinsonism–
dementia complex (ALS/PDC) that had an extremely high rate of incidence among the
Chamorro people of
Guam. The Chamorro call the condition
lytico-bodig. No demonstrable
heritable or
viral factors were found for the disease, and a subsequent decline of ALS/PDC after 1963 on Guam led to the search for responsible environmental agents. The use of flour made from cycad seed (
Cycas micronesica) in traditional food items decreased as that plant became rarer and the Chamorro population became more Americanized following World War II. Cycads harbor symbiotic
cyanobacteria of the genus
Nostoc in specialized roots which push up through the leaf litter into the light; these cyanobacteria produce BMAA. In addition to eating traditional food items from cycad flour directly, BMAA may be ingested by humans through
biomagnification.
Flying foxes, a Chamorro
delicacy, forage on the
fleshy seed covering of cycad seeds and concentrate the toxin in their bodies. Twenty-four specimens of flying foxes from museum collections were tested for BMAA, which was found in large concentrations in the flying foxes from Guam. As of 2021 studies continued examining BMAA biomagnification in marine and estuarine systems and its possible impact on human health outside of Guam. Studies on human brain tissue of ALS/PDC, ALS,
Alzheimer's disease, Parkinson's disease,
Huntington's disease, and neurological controls indicated that BMAA is present in non-genetic progressive neurodegenerative disease, but not in controls or genetic-based Huntington's disease. research into the role of BMAA as an environmental factor in neurodegenerative disease continued. == Clinical trials ==