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A Dietary Cause for a Neurodegenerative Disease

This is an interesting paper in itself, and its potential implications are even more so. The authors, from the Institute for Ethnomedicine and the University of Miami, have been studying a neurodegenerative condition found among Chamorro villagers on the island of Guam. The disease (Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex) is characterized by neurofibrillary tangles and beta-amyloid plaques, which puts it right in the middle of a number of other well-known CNS pathologies.

Over the years, it’s been determined that the causative factor is likely beta-N-methylamino-L-alanine (BMAA), which is thoroughly mixed into the local food chain via exposure to cyanobacteria. This new paper details primate studies which show that exposure to this amino acid in the diet is sufficient to bring on the neuropathology, which further strengthens the link. BMAA is apparently substituted for serine in various proteins, to bad effect, and supplemental L-serine has been previously shown to prevent BMAA uptake in cell culture. This new paper also shows that this can prevent the effects seen in the feeding studies.

BMAA-producing cyanobacteria occur globally, perhaps causing similar neuropathologies. Our finding that all of the low-dose vervets developed tauopathies with NFT has implications for human health. BMAA may serve as an environmental trigger for some forms of other neurodegenerative illnesses including sporadic ALS and AD. In human beings, increasing age is a risk factor for ALS, AD and PD. We have initiated experiments to determine if chronic dietary exposures of aged vervets to BMAA results in more profound histopathology.

This reminds me of the work suggesting that exposure to mitochondrial toxins may be a risk factor for Parkinson’s. There’s clearly a lot to learn about these pathways. On one level, it may seem too easy to reach for an environmental cause for these things, but you definitely can’t rule out the idea. Perhaps it’s just a contributory factor in some patients, or it may be something more.

30 comments on “A Dietary Cause for a Neurodegenerative Disease”

  1. Anon says:

    Obvious question: Have there been any tox studies on BMAA in rats?

    1. Me says:

      They would need to be some extremely long-term tox studies!

      But nonetheless an interesting piece of work. Could offer a piece of the puzzle (like maybe the mechanism by which this amino acid is discriminated against in vivo breaks down with age – that wouldn’t surprise me at all; or incorporation of this A.a. leads to increased ROS in vivo [come on Lane Simonian!!])

      Another point: are there any patient sub-populations that take serine supplements as a therapeutic intervention….and have they been followed for incidence of neuroD diseases.

      1. Snark says:

        @Me 9:49 am

        I don’t recall Lane Simonian posting here any more after “Solve the math problem” spam filter was added.

        1. Anon says:

          Thanks, I just spat coffee all over my keyboard! :-/

        2. Ha ha says:

          Maybe Lane is actually a spambot, not a real person. That would explain, well, everything!

    2. Erebus says:

      Maitham Ahmed Al-Sammak, Douglas G. Rogers, and Kyle D. Hoagland, “Acute β-N-Methylamino-L-alanine Toxicity in a Mouse Model,” Journal of Toxicology, vol. 2015, Article ID 739746, 9 pages, 2015. doi:10.1155/2015/739746

      “In conclusion, the presumptive LD50 of L-BMAA is 3 mg/gm BW and the LOAEL of L-BMAA is 2 mg/g BW in male and female NIH Swiss Outbred mice when administered intraperitoneally, and this animal model may prove useful for investigating the role of L-BMAA in neurodegenerative diseases.”

      (Which surely makes BMAA the most acutely toxic amino acid?)

      …Anyhow, that paper references other tox studies which are also interesting.

      1. John Adams says:

        I suspect Ethionine is more toxic?

  2. Anon says:

    Next question: Could this mouse model be useful for testing drugs against AD and/or other amyloid/tau-related neurodegenerative diseases?

    1. me says:


      From the info printed on this page, I’d suggest the assay is not fit for purpose. Intraperitoneal injection is injection directly into the body cavity – we are unlikely to ingest amino acids via this route. I’d imagine the study that would prove it would be a long-term study where the mice are fed a diet rich in the A.a in question, with a control group, and potentially an escalating dose, then maybe a follow-up where you intervene with serine to see if it rescues.

      Results would probably take months/years to read out depending on life expectancy of the mice.

      There you go. Propo0sal written.

      Derek let’s crowd-fund it. The mice can live at your place 🙂

      1. Erebus says:

        The fulltext of that paper (which is freely available at dx.doi. org /10.1155/2015/739746) references a couple of studies like that….

        T. L. Perry, C. Bergeron, A. J. Biro, and S. Hansen, “β-N-methylamino-L-alanine. Chronic oral administration is not neurotoxic to mice,” Journal of the Neurological Sciences, vol. 94, no. 1–3, pp. 173–180, 1989.

        R. Cruz-Aguado, D. Winkler, and C. A. Shaw, “Lack of behavioral and neuropathological effects of dietary β-methylamino-L-alanine (BMAA) in mice,” Pharmacology Biochemistry and Behavior, vol. 84, no. 2, pp. 294–299, 2006.

        …But doesn’t attempt to explain why oral dosing, as opposed to IP dosing, does not appear to be neurotoxic in mice. In any case, I agree that the IP model isn’t a good fit. I’d suggest a higher-dose, longer-term (16+ week) oral toxicology study.

        (It is interesting that IP administration is so acutely toxic, though.)

        1. Morten G says:

          So we can safely conclude that mice/rats don’t get tau pathology / amyloid plaques from BMAA. Isn’t it really hard to give a rodent Alzheimer’s?
          Vervets aren’t a practical experimental animal but try a bunch of animals and one will show up with something similar to the holes in human brains. Hopefully guinea pigs or similarly tiny. Screening rather than working from first principles like they did in this paper (and such a nice paper it is! really a good read).
          Wikipedia actually has a ton of stuff on the subject. I’m going to risk it and post a link: (click through to BMAA).

      2. Matthew K says:

        “Intraperitoneal injection is injection directly into the body cavity – we are unlikely to ingest amino acids via this route.”
        Actually that’s functionally exactly how we ingest AAs – injecting into the peritoneal cavity means that the uptake is via the mesenteric vessels – i.e. the hepatic portal vein. AAs from food digestion are absorbed by the intestine and delivered to the portal vein as well. Granted, there will be some bypass if they are taken up by the vascular beds of the other viscera, but by far the largest absorptive surface in that area is the mesentery.

        1. NJBiologist says:

          Materials delivered to the gut lumen have to be moved out in order to access the mesenteric circulation. This is often done by transporters (pretty much all amino acid transport is by a small family of transporters); this introduces saturability of transport, as well as competition and affinity issues. Net result, IP is not always the same as PO (and we haven’t even talked about the effects of salivary enzymes and stomach acid…).

  3. Nately says:

    Puh-leeze, long since proven to be due to peroxy nitrates

    1. me says:

      nitrItes dear boy. get it right or the ROS Gods will strike you down.

  4. Chris Swain says:

    You may need many years of exposure for toxic effects to become apparent?

  5. Vader says:

    Google (all hail the font of all human knowage) informs us that this amino acid is present in shark fins.

    I think I’ll skip lunch at the local McChinese.

  6. Lane Simonian says:

    I like it how people enjoy pushing my buttons (or on rare occasion encourage me to comment). At least we have determined that I can solve simple math problems.

    But to the matter at hand. Here is the connection between BMAA and oxidative stress.

    And to go further afield. A series of pollutants/environment toxins that increase oxidative stress have been tentatively linked to Alzheimer’s disease. These include but are not limited to aluminium fluoride, diesel fumes, particulate matter, mercury, industrial solvents such as toulene and benzene, and pesticides such as DDT and Agent Orange (dioxins).

    As a Latin American environmental historian, I especially appreciated a recent study that showed children exposed to high levels of air pollution in Mexico City displayed subtle cognitive dysfunction. Many of these children (especially with the Apoe4 gene) had diffuse amyloid plaques and hyperphosphorylated tau in their brains (but of course not Alzheimer’s disease). When given cocoa (a peroxynitrite scavenger) their cognitive function improved somewhat.

    One last far afield yet tangentially relevant comment. Amyloid plaques may sequester infectious prion proteins and thus to a certain extent be neuroprotective (or perhaps more accurately they stop the production of hydrogen peroxide by absorbing copper and zinc).

    Diet, genetics, environmental toxins, certain medications, certain chronic bacterial, viral, and fungal infections, lifestlye choices, and stress may all contribute to Alzheimer’s disease and perhaps to other forms of dementia.

    1. Farmhand says:

      So much nicer and far, far classier, to see information, however questionable to some people, than stupid snarky ad hominem put-downs. Well done, Lane.

    2. Squib says:

      Lane, as much as I don’t truly buy into your radical hypothesis, it is always fun to see you post. I mean this in a completely genuine way

  7. InfMP says:

    Derek, you should do a day in the life of the medchemist writeup:

  8. Lane Simonian says:

    Better yet for the possible connection between BMAA and several neurodegenerative diseases.

  9. Mark Thorson says:

    In a survey of cyanobacterial species, 95% of the genera tested and 97% of the strains tested contained BMAA.

    One of the species which has BMAA at a high level is Aphanizomenon flos-aquae. A Google search will reveal that there’s lots of people who want to sell you supplement pills containing AFA harvested from a lake in Oregon.

  10. Tuck says:

    It’s not the first case of diet-caused neurodegenerative disease, of course. “Mad cow” and CJD are obvious examples, and there’s this paper reviewing the many neurological and neurodegenerative diseases associated with wheat consumption:

    “Neurological presentation of celiac disease”

  11. Norbert Schtumpf says:

    The mycotoxin 3-nitropropionic acid was identified as a neurotoxic inhibitory of Complex II of the mitochondrial respiratory chain after a cluster of people in China developed Huntington’s Disease-like symptoms. It was traced to fungi on sugar cane, and 3-NP is now used in animal models of mitochondrial dysfunction and HD.

    1. Mark Thorson says:

      It’s not just sugar cane. According to Wikipedia, several fermented Japanese foods also contain it.

      This reminds me of the situation with aflatoxins. Back in the 60’s or 70’s when the magnitude of the problem was becoming known, it was discovered that there was some type of Japanese fermented soybean paste that was very rich in aflatoxins, and it was blamed for the high rate of stomach cancer in Japan. I presume they don’t make that stuff any more, or make it in a different way.

  12. Mark Thorson says:

    Some cynaobacteria make D-amino acids. I wonder what mischief those might cause.

    1. Erebus says:

      The typical ones are absolutely harmless at any reasonable dose. Some — D-methionine, D-serine, D-aspartic acid, among others — are pharmacologically interesting & potentially useful.

      Aside: John Adams above is right. Ethionine appears to be the most acutely toxic small amino acid, but only in its D- form. The L stereoisomer is roughly 10x less toxic… which is still very bad.

  13. Andre says:

    Derek, very nice post with potentially important implications for the understanding of late-onset neurodegenerative diseases. The rescue by coadministration of serine is a nice control in the study. What is however missing in the present study is the proof that the observed tau tangles and amyloid precursor protein deposits contain indeed peptides harbouring methylamino-alanine in place of serine. This would significantly strengthen their hypothesis!

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