Monkeys fed a diet of the cyanobacterial toxin BMAA develop neuropathology that mimics that seen in Guamanian ALS/parkinsonism dementia complex (ALS/PDC), and simultaneous consumption of L-serine can partially prevent that neuropathology, according to a study led by Paul Cox and Sandra Banack of the Institute for Ethnomedicine in Jackson Hole, Wyoming, and published January 20 in Proceedings of the Royal Society B. The study provides evidence that BMAA exposure may underlie the high incidence of ALS/PDC among the Chamorro people of Guam and elsewhere, but whether this environmental toxin contributes to sporadic ALS remains unclear.
The cause of ALS/PDC has been controversial since the recognition of the syndrome by military physicians in the 1950s. BMAA (beta-N-methylamino-L-alanine) is a nonstandard amino acid isolated from cycad seeds, which are ground into flour used by the Chamorro, and bioconcentrated in flying foxes, also part of the Chamorro diet (see Nov 2003 Alzforum News). BMAA is a product of cyanobacteria, which live in symbiosis with cycads. Early experiments established its potential as an acute neurotoxin, but the contributing role of chronic exposure at dietary doses has been a matter of debate.
“The major weakness with the BMAA theory has been the lack of an animal model that demonstrates that chronic exposure to BMAA produces neuropathology consistent with ALS/PDC,” stated the study’s corresponding author, Paul Cox. To address that weakness, Cox and colleagues fed cohorts of four juvenile vervet monkeys, daily for 140 days, pieces of fruit containing either 651 mg (210 mg/kg) BMAA, 651 mg L-serine, both BMAA and serine, or 651 mg rice flour as a placebo. The cumulative dose of BMAA was approximately 10 times the calculated lifetime exposure among the Chamorro. Cox and colleagues have previously shown that L-serine can prevent misincorporation of BMAA into proteins (see Oct 2013 news).
Monkeys fed BMAA alone developed tau-positive neurofibrillary tangles and sparse amyloid plaque-like deposits in multiple brain regions. Similar pathology was not seen in monkeys fed only serine or placebo, and was only 10% to 20% as prevalent in those fed both BMAA and serine. In a second experiment, cohorts of 8 adult vervets each were fed as before, except for a higher dose (987 mg) of test material in keeping with a larger body size, and a new group was added, which received 98.7 mg BMAA daily, to approximate the calculated lifetime Chamorro exposure. Again, BMAA exposure was associated with formation of plaques and tangles, and showed a dose-response relationship in multiple brain regions, with tangle density in the high-dose group twice as great as in the low-dose group. In some regions, including the primary motor cortex, high-dose BMAA produced pathology, while pathology in those receiving the low dose was no different from control. Again, co-administration of serine and BMAA reduced neuropathology, by 35% to 50%, depending on the brain region.
Protein-bound BMAA was detected in brain tissue of monkeys fed BMAA, but not control monkeys. The concentration was similar to that in brain tissue of ALS/PDC patients, “confirming that BMAA exposures in the vervets are clinically relevant,” Cox said. No clinical symptoms were observed, but this would be expected based on the degree of pathology, which is reminiscent of preclinical Alzheimer’s disease (AD), according to Cox. Study of a group of older living monkeys exposed to BMAA is ongoing.
“The fact that BMAA-dosed vervets produced neurofibrillary tangles and rare beta-amyloid deposits in both experiments supports the theory that BMAA in the traditional diet is a cause of the Chamorro disease,” Cox and colleagues concluded. Further, Cox said, the fact that the toxin appears to elicit both forms of AD pathology in a single animal model may make it useful in developing treatments that address both plaques and tangles.
“This study shows that if you give BMAA to vervets, you produce the pathological changes seen in the Guam patients,” said Walter Bradley of the University of Miami, who was not involved in this study, but has studied BMAA in ALS/PDC, “The field has been asking for a primate model for a long time, and this paper provides it.”
Since the links to cycad and flying fox consumption were proposed, the Chamorro diet has changed, and the incidence of ALS/PDC has dropped dramatically. While providing strong evidence for a role for BMAA in Guamanian ALS/PDC is valuable, Bradley said, the greater interest lies in whether this is a model for neurodegenerative disease more generally, including sporadic ALS. The pathology is not that of “classical” ALS, but he noted that there are many cases of ALS that don’t display the standard pathology. “The fact that ALS in the United States does not generally show neurofibrillary tangles and plaques does not rule out that BMAA could play a role in sporadic ALS in the US,” he said.
“This new study reports impressive findings, but the study is small and much more work is needed to confirm and extend these findings”, said John Trojanowski of the University of Pennsylvania. He noted that very little has been published on the use of vervets as a model of neurodegenerative disease, “Thus, there are few other studies to look at for comparison with the current study,” he said. Given that the median number of neurofibrillary tangles (NFT) in the control vervets was, in some brain areas, almost 25% of that in the high-dose group, it will be important to validate these results in larger cohorts of vervets to see “whether or not these results will hold up”. He added that “there is a specific AD-like biochemical signature for tau pathology in Guam ALS/PDC subjects (Trojanowski et. al., 2002), so it would also be important to demonstrate this signal in the vervet model”.
TDP-43 pathology has been reported in Guamanian ALS-PDC patients, Trojanowski noted, and it would be valuable to look for similar inclusions in the BMAA-treated vervets. Cox and colleagues are beginning that work, as well as looking at spinal cord pathology, to determine if there is a stronger link to ALS outside of Guam.
Epidemiological studies are ongoing (see June 2010 News), examining BMAA exposure in ALS cohorts and searching for ALS clusters in areas known to be high in BMAA, including lakesides and deserts receiving intermittent flooding. The challenge, said Bjorn Oskarsson of the University of California at Davis, who studies ALS epidemiology and was not involved in the BMAA study, is that BMAA is widespread and ALS is rare, and anyone who develops ALS has been exposed to many other things as well. “We are still struggling to make a specific epidemiological connection to ALS,” he said.
“This is a beautiful study that shows that BMAA has a neurotoxic effect, but the question of relevance beyond ALS/PDC remains open. It’s possible, but it is hard to make that extrapolation from this study.”
Cox PA, Davis DA, Mash DC, Metcalf JS, Banack SA. Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain. Proc Biol Sci. 2016 Jan 27;283(1823). [PubMed]