A paper published today suggests that chronic exposure to an environmental toxin may increase the risk of neurodegenerative illnesses such as Alzheimer’s disease.
For the first time, researchers have shown that feeding vervets a toxin found in blue green algae resulted in protein deposits in the brain, consistent with those seen in human Alzheimer's.
Whilst the cause(s) of most neurodegenerative disease remains largely unknown, it is expected that a gene/environment interaction will eventually be identified. Around 5-10 % of cases are caused by genes, but the role of environmental factors in these illnesses is poorly understood.
Owing to its role in an unusual illness suffered by Chamorro villagers on the Pacific Island of Guam, an algal toxin called BMAA, (Beta-Methylamino-L-alanine) has been investigated for over 40 years. BMAA was first discovered when scientists were searching for the causes of the fatal illness that had symptoms of Alzheimer’s, motor neurone (MND) and Parkinson’s disease and at its peak, killed over 25% of the male population of one village.
For the first time, researchers have shown that feeding vervets a toxin found in blue green algae resulted in protein deposits in the brain, consistent with those seen in human Alzheimer's.
When efforts to find a genetic link had been exhausted researchers looked for an environmental trigger. They found blue green algae growing in the roots of cycad tress, a staple foodstuff of the Chamorros, and a toxin produced by the algae had concentrated in the seeds of the plant.
The study published today in the Royal Society Proceedings B recreates experimentally the pathology seen in these people by using chronic administration of BMAA in food. Three groups of vervets were fed fruit for 140 days, some with BMAA, some with placebo and some with a known inhibitor of BMAA, an amino acid called L-serine.
In all the animals fed BMAA, tangles and plaques were detected in their brain tissue, but not in the placebo animals. This is the first time researchers have been able to successfully produce brain tangles and amyloid deposits in an animal model through exposure to an environmental toxin.
In all the animals fed BMAA, tangles and plaques were detected in their brain tissue, but not in the placebo animals.... in combination with L-serine showed a highly significant reduction in the number and density of protein tangles
Even more compelling was the vervets fed BMAA in combination with L-serine showed a highly significant reduction in the number and density of protein tangles. L-serine was first reported to block BMAA toxicity in cell culture back in 2013, but this is the first evidence it can prevent the formation of protein deposits in the brain.
The path from dementia to discovery – set backs in implicating BMAA in disease.
The story of BMAA as a neurotoxin has a long and chequered history. In the 1950s, US physicians reported a puzzling neurodegenerative illness in the indigenous Chamorros of Guam that manifested as dementia, Alzheimer’s, Parkinson’s and Motor Neurone Diseases. In the 1960s, Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) was described based on protein tangles in the brain and clinical symptoms which resemble the various symptoms of this disease.
A search for an environmental trigger led to an investigation of cycad flour, as this served as a staple foodstuff by the indigenous people, used to make tortillas, and thicken soups.
The impetus for this stemmed from another neurological disease called Lathyrism which was caused by an unusual amino acid (ODAP) found in legumes of the genus lathyrus sativus. Neurolathyrism manifested as an acute paralysis and may have been implicated in the death of Chris McCandless aka “Alexander Supertramp” whose emaciated corpse was found in the wilderness of Alaska. Whilst it was initially thought he died of starvation it now seems likely the starvation was a result of paralysis caused by eating grass peas meaning he was unable to scavenge for food.
But in order to prove that a substance is a causative agent, it needs to satisfy Koch’s postulates and these include demonstrating that when inoculated into a healthy, susceptible laboratory animal, it can cause the disease.
So, in the 1980s, BMAA was fed to macaques and found to cause acute neurological symptoms [10], but this finding was discounted when it was argued that an equivalent human dose would require the consumption of more than 1000 kg of cycad seed flour [11]. However, the observation that the majority of BMAA in cycad seeds binds to proteins and cannot be released by washing with water, suggested that the BMAA doses ingested by the Chamorros had been previously underestimated [14,15].
Meanwhile, evidence continued to build for the link between BMAA and neurodegenerative disease with respect to cyanobacterial exposure and epidemiology. For example, it was reported that people who consume large quantities of seafood from waters contaminated with blue green algae had a higher risk of contracting MND.
An elegant study mapping MND patients’ place of residence showed those who lived on the leeward side of water bodies that had regular algal blooms were at a greater risk for disease. This suggests that ingestion is not the only route for exposure but inhalation of BMAA may also play a role. This hypothesis is supported by observations that soldiers who fought in the gulf war also have an increased risk of contracting MND and over 60% of the desert crusts of Qatar contain BMAA. BMAA was found to bioaccumlate up the food chain from crabs, to pelagic fish to sharks.
A key missing puzzle piece was how BMAA might stick to proteins as was seen in the cycad flour. And it was not until 2013 that a plausible explanation was presented. In a paper on which I was first author, we showed that BMAA had a structure similar enough to an amino acid humans already use to make proteins. We showed that BMAA could be swapped for L-serine when cells make proteins, rendering the proteins toxic and causing the cells to commit suicide.
This was a critical discovery because it finally offered an explanation for how BMAA might be stored in the brain. And for this we need to look to brain cells and their renewal. Neurons, unlike other cells in the body, are not turned-over very often, so they are unable to dispose of damaged or toxic proteins as efficiently as say hair or skin cells. This means they might act as a reservoir for BMAA, locking it up inside their proteins, where it can do damage years later.
The findings of today's study are significant – not only because they provide evidence for what we've long suspected – but also because they implicate a ubiquitous toxin in a growing and formidable human health problem. BMAA is made by blue green algae (more accurately known as cyanobacteria) which manifest as characteristic bright green blooms in bodies of water. The problem is these blooms are increasing in size and frequency as global temperatures rise. And Australia is particularly susceptible, historically having had the world's largest ever fresh water algal bloom that occurred in the summer of 1991–92.
Cyanobacterial mats in Yellowstone National Park. Pretty but toxic.
So if BMAA is already enriched in the environment, it follows that we've all been exposed to some degree, so why don't we all have neurodegeneration? As previously noted, it's likely that the trigger for the disease is a combination of genes and environmental factors, and also the process probably requires many years. But at least now we have a model to explore ways to prevent or even cure the disease.
What we do know is what we've long suspected – BMAA can cause disease in susceptible individuals.