L-serine, a naturally occurring amino acid, and Alzheimer’s disease

Today, a press release issued by researchers at the University of California, San Diego argued that L-serine could be dangerous for consumption.

In a letter to Cell Metabolism the researchers contested previous findings by scientists in France who found that L-serine was effective at reducing cognitive deficits in mice that exhibit aspects of Alzheimer’s disease.

L-serine is a naturally occurring amino acid synthesized by the body and is abundant in food.

While not disputing the cognitive benefits of L-serine, the San Diego team cautioned against
L-serine consumption because they found an increase of the enzyme PHGDH in mice with Alzheimer’s mutations as well as in the hippocampus of human Alzheimer’s patients.

PHGDH is the first step in a three-step enzymatic process within the brain that synthesizes
L-serine.

The San Diego researchers speculated that if PHGDH is increased, L-serine levels might also be increased. However, these researchers did not measure L-serine in the brain, nor did they perform any clinical studies. 

The Brain Chemistry Labs has been studying L-serine as a possible treatment for ALS and Alzheimer’s disease.

In FDA-approved clinical trials, no serious adverse effects have been found in patients taking
L-serine up to 30 grams per day. Furthermore, residents of Ogimi village in Okinawa, many of whom are over 100 years old, have not noted negative effects from their diet which is extremely rich in L-serine. Extensive studies of L-serine in laboratory animals have also failed to find any adverse effects of high-dose L-serine.

 The Brain Chemistry Labs does not encourage individuals outside of the clinical trials we are sponsoring to take L-serine until the FDA approves L-serine for the treatment of neurodegenerative diseases.

Additional information: 

P.A. Cox, et al. 2016. Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain. DOI: https://doi.org/10.1098/rspb.2015.2397

 P.A. Cox, J.S. Metcalf. 2017. Traditional food items in Ogimi, Okinawa: L-serine content and the potential for neuroprotection. DOI: https://doi.org/10.1007/s13668-017-0191-0

 J. Metcalf, et al. 2018. L-serine: a naturally-occurring amino acid with therapeutic potential. DOI: https://doi.org/10.1007/s12640-017-9814-x

 J. Le Douce, et al. 2020. Impairment of glycolysis-derived L-serine production in astrocytes contributes to cognitive deficits in Alzheimer’s disease. DOI: https://doi.org/10.1016/j.cmet.2020.02.004

 X. Chen et al. 2022. PHGDH expression increases with progression of Alzheimer’s disease pathology and symptoms. DOI: https://doi.org/10.1016/j.cmet.2022.02.008

Initial SWFL study finds water, air pollutants could cause grave brain disease.

By: Amy Bennett Williams

Fort-Myers News-Press
Published 12:25 pm E.T. May 2, 2022 | Updated 2:12 pm E.T. May 2, 2022.

The good news: A first-of-its-kind field study of Southwest Florida air and water didn’t find widespread cyanobacteria toxins – mostly.

The bad news: It did find several neurotoxins as well as three forms of BMAA, a neurotoxin linked to grave brain diseases.

Two of the forms were in every one of 945 analyses done over five months between last July and November by Calusa Waterkeeper volunteers and analyzed at Wyoming’s Brain Chemistry Labs.

The results were released Monday.

Researchers call the neurotoxins’ presence ubiquitous and concerning.

Health policymakers have yet to weigh in. Neither the Florida Department of Health in Lee County nor the state Department of Environmental Protection conducts cyanotoxin air sampling.

Because no study of this kind has been done, the public health implications aren’t yet clear, and more research is needed before they are, says Paul Cox, executive director of Brain Chemistry Labs.

“Are the toxins there? Yes. Are they being airborne? Yes. Are they bad news? Yes,” said Cox. “I’m sorry we don’t have firmer answers (but) citizens are really concerned about this – correctly concerned.”

Though cyanobacteria, also called blue-green algae, has long been studied, research on its human health effects is ongoing on several fronts. Universities, government agencies, and nonprofits like Waterkeeper all are looking at different aspects.

This effort is the first to sample both air and water on-site with a custom-engineered monitoring device dubbed ADAM: airborne detection for algae monitoring, designed in collaboration with algae scientists, including Michael Parsons at Florida Gulf

Coast University, a member of the state’s Blue-Green Algae Task Force.

That acute exposure can make people sick and kill dogs is not in question. Longer-term effects are less clear, but algal toxins have been linked to a number of serious illnesses, including liver cancer and neurodegenerative diseases like ALS and Parkinson’s that may take years after exposure to develop.

Also not in question: Inhalation increases the toxins’ potency, exposing them directly to the bloodstream, says Calusa Waterkeeper John Cassani. Yet there are no federal or state guidelines on exposure, he said.

That’s why his nonprofit teamed up with nonprofit Brain Chemistry Labs to do what the government doesn’t: check the air for toxins produced by cyanobacteria.

The study aims to arm the public with basic information on the toxins they may be encountering in their daily lives.

“We all have a right to know the human health impacts of harmful algal blooms,” said board president Jim Watkins.

Volunteer scientists collected air and water from eight Lee County locations, from Matlacha to Punta Rassa and up the Caloosahatchee River to Alva, then samples went to Wyoming for pro bono analysis.

It’s important to note that these results are from a period without major blooms – a relatively calm stretch, algae-wise. Had they been sampling mid- bloom the results might have been quite different, says scientist and Waterkeeper volunteer Manuel Aparicio, who led the project to develop the device.

“The goal of our work is to inform the public,” Aparicio said. “We’ve established the method ... we’ve set up a program. We’ve got rangers, we’ve got the device (and) we’re going to continue to do this.”

‘Concerning’ molecule

One neurotoxin that appeared consistently is beta-Methylamino-L-alanine, known as BMAA.

BMAA is a compound with a fixed number of carbon, nitrogen, hydrogen, and oxygen atoms said Brain Chemistry Labs scientist James Metcalf. “These atoms can be arranged in different ways resulting in different compounds with the same mass. BMAA has 2 isomers – AEG and DAB – in cyanobacteria with the same mass and numbers of atoms. Therefore, it is important to make sure that you can identify each one separately and we did this in our analyses.”

Their presence is worrisome because a recent paper strongly associated BMAA with neurodegenerative disease and concluded BMAA “most likely could cause ALS,” Metcalf said. Both of its isomers have also shown neurotoxicity in animal models.

But how much makes people sick is an open question.

“We certainly need to do more air sampling to get a better picture of our airborne exposure,” Metcalf said.

In the meantime, “People should avoid exposure to blooms and scums ... We certainly need to do more research to understand the risk of airborne exposure and this may influence future policy.”

Cox agrees. “The scientists are uncertain if the doses are enough to trigger disease,” said Cox. “We just don’t know, and it would be irresponsible of me to indicate otherwise, but I am concerned. “What I don’t want to see is a book that comes out in 10 or 20 years and has a chapter called ‘The Florida Incident.’”

New Alzheimer’s Biomarker May Facilitate Rapid Diagnosis

Blood test collection tube saying "Alzheimer's Disease"

Discovery of a unique ratio of metabolites from blood samples of early-stage Alzheimer’s patients promises to speed diagnosis of Alzheimer’s disease.

Although symptoms of advanced Alzheimer’s disease are well known, diagnosis of Alzheimer’s disease in its earliest stages requires careful cognitive testing by neurologists.

Discovery of a unique ratio of metabolites from blood samples of early-stage Alzheimer’s patients promises to speed diagnosis, allowing earlier treatments to be initiated.

“We were delighted to discover that the ratio of two molecules, 2-aminoethyl dihydrogen phosphate and taurine, allows us to reliably discriminate samples of early-stage Alzheimer’s patients from controls,” said Dr. Sandra Banack, lead author of the report in PLOS ONE and Senior Scientist at the Brain Chemistry Labs in Jackson Hole.

Dr. Sandra Banack works on the amino acid analyzer in the Brain Chemistry Labs, Jackson, Wyoming.

The blood samples were drawn from patients enrolled in an FDA-approved Phase II trial at Dartmouth Hitchcock Medical Center in New Hampshire and then shipped to the Brain Chemistry Labs for analysis. Current attempts to diagnose Alzheimer’s disease from blood samples depend on the presence of amyloid fragments, the molecules that cause brain tangles and plaques.

“At the Brain Chemistry Labs, we consider amyloid plaques to be a consequence rather than the cause of Alzheimer’s disease,” Dr. Paul Alan Cox, Executive Director of the Brain Chemistry Labs explains. “What is exciting about this new discovery is that it does not depend on amyloid and the assay can be performed on analytical equipment that is already present in most large hospitals.”

Their report, written with Alzheimer’s expert Dr. Aleksandra Stark, “A Possible Blood Plasma Biomarker for Early-stage Alzheimer’s Disease” is being published this week in PLOS ONE.

About the Brain Chemistry Labs: The Brain Chemistry Labs is a not-for-profit research institute based in Jackson Hole focused on improving outcomes for patients suffering from Alzheimer’s, ALS, and other neurodegenerative illnesses.

Contacts:
Dr. Sandra Banack, Tel: 307-734-1680, sandra@ethnomedicine.org
Dr. Paul Alan Cox, Tel: 801-375-6214, paul@ethnomedicine.org

Download our press release here

Epidemiological Study Finds Cyanobacterial Toxin BMAA Causes ALS

An important new article on ALS epidemiology strongly supports the hypothesis that the cyanobacterial toxin BMAA causes ALS, a devastating paralytic disease that can strike people down in the prime of life.


At the Brain Chemistry Labs, we have years of research to support our theory that BMAA is linked to ALS. Now a study from independent researchers also reports a link, strengthening our claims.

Although genetic factors have been extensively researched, only 8-10% of ALS cases are familial. Environmental factors are believed to play an important role in the remaining 90-92% of cases that are sporadic.

 Researchers at Arizona State University reviewed 1,710 scientific papers in an effort to rank possible environmental factors that potentially cause ALS. They used the Bradford Hill criteria, which is a way of measuring risk factors for disease causality.

The top supported environmental ALS risk factor emerged: the cyanobacterial toxin BMAA, which is the only environmental factor that met all nine Bradford Hill criteria. The next most likely risk factor, formaldehyde, on the other hand, only met five Bradford Hill criteria.

Dr. Paul Cox at the Brain Chemistry Labs, who was not associated with this paper, clarifies that while BMAA emerges from the new study as the best-supported causative factor, “it does not mean that exposure to BMAA or cyanobacterial toxins is the most common cause of ALS. A combination of genes and other environmental factors likely play an important role.”

The researchers concluded: “BMAA, formaldehyde, manganese, mercury, and zinc emerged as the five highest-ranked environmental factors through a combination of Bradford Hill criteria analysis and association analysis of population exposure studies.

These are the environmental toxins most recommended for the most immediate research. Due to extensive research of BMAA over the years, this analysis asserts causal criteria have been met.”

The researchers also specifically attribute population-wide BMAA exposures to consumption of contaminated seafood:

“When aligning the results from the systematic review of ranked factors with those obtained by the state-of-the-science population exposure assessment, BMAA exposures likely were derived from the ingestion of seafood harvested from waters contaminated with cyanobacteria or from ingestion of the cycad plant.”

The researchers note the importance of measuring BMAA in cyanobacterial blooms which requires trained scientists using expensive laboratory equipment.

The Brain Chemistry Labs has developed a lateral flow immunoassay, much like a pregnancy test, which promises to provide a rapid and inexpensive way to detect BMAA by water managers, fishermen, and laypeople who are concerned with cyanobacterial blooms.   

Newell ME, Adhikari S, Halden RU. Systematic and state-of-the-science review of the role of environmental factors in Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's Disease. Science of The Total Environment. 2021 Dec 28:152504.

Can We Transform the Diagnosis & Treatment of ALS?

In 1874, Jean-Martin Charcot described a devastating paralytic illness which we now call ALS.

ALS cuts down people in the prime of their lives.

Only two FDA-approved drugs exist for the treatment of ALS, and neither significantly slow disease progression.

We have focused on the early diagnosis and treatment of ALS.

We discovered a molecular fingerprint of ALS, which will allow neurologists to definitively diagnose ALS based on a single blood draw. We extract microRNA from exosomes—microscopic packages of genetic material—in the blood sample. The unique assemblage of microRNA identifies ALS patients.

Currently, many patients have to wait a year or more to receive an ALS diagnosis. This new diagnostic test will allow patients to begin treatment much earlier.

Our advanced clinical trials of the naturally occurring amino acid L-serine are promising.

Hopefully, this combination of a diagnostic and a treatment package will be attractive to a pharmaceutical partner who can conduct the larger clinical trials that will be needed.

Dr. Sandra Banack prepares an ELISA plate to measure exosomes.





Happy Birthday Yellowstone National Park!

Grand Prismatic Spring in Yellowstone National Park. Photo credit: Dr. Paul A. Cox

One hundred and fifty years ago today, on March 1, 1872, the first National Park in the world, Yellowstone was created by the United States Congress and signed into law by President  Ulysses S. Grant.

National parks, termed by documentary filmmaker Ken Burns as “America’s Best Idea” have continued since that time to be created, including the 50 th National Park of the United States in American Samoa, in which our Executive Director Dr. Paul Alan Cox, played a key role.

Happy Birthday, Yellowstone!

National Park of American Samoa. Photo credit: nps.gov

Compound from violets may help fight glioblastoma

NEWS RELEASE 26-JAN-2022

BRAIN CHEMISTRY LABS

A circular peptide derived from violets could lead to new approaches in treating glioblastoma, a highly aggressive form of brain cancer.

(Jackson, Wyoming—January 26, 2022) – A circular peptide derived from violets could lead to new approaches in treating glioblastoma, a highly aggressive form of brain cancer.

Researchers report that cyclotides, small circular proteins produced by violets increase the power of TMZ, a chemotherapeutic agent, in killing human glioblastoma cancer cells. 

Glioblastoma is a fatal type of brain cancer of adults and children with a median survival time of 9-16 months from diagnosis. Half of the tumors are resistant to the only FDA-approved treatment, TMZ, and the remainder quickly evolve resistance to this chemotherapy. Combining cyclotides with TMZ can increase the ability of TMZ to kill glioblastoma cells up to eight-fold, researchers report.

“We think we are on a path that could lead to better treatment of glioblastoma in the future,” reports Dillard University Professor Samantha Gerlach, lead author of the report published last week in the Journal of Natural Products. 

The biggest hurdle faced by researchers working in the laboratories based in Wyoming is extracting enough of the compounds from violets to test. Kilograms of violets are needed to yield a tiny dose.

“Our cell culture studies, though encouraging, are far from being useful in a clinical setting,” cautions Dr. Paul Alan Cox, Director of the non-profit Brain Chemistry Labs in Jackson Hole. “Just extracting enough cyclotides to test in mice will take months.”

Despite these technical obstacles, the research team remains undaunted. “Patients, particularly children, diagnosed with glioblastoma have few options,” says Dr. Samantha Gerlach. “Our goal is to eventually provide new hope to glioblastoma patients and their families.”

Find the original research here

Novel Glioblastoma Treatment – New Publication

Cyclotides are a group of compounds found in violets

Together with visiting scientist Dr. Samantha Gerlach, we found that circular proteins called cyclotides extracted from violets could allow us to reduce eight-fold the dose of TMZ, a chemotherapeutic agent for glioblastoma.

This would slow the evolution of drug resistance of brain cancer cells to TMZ. We are now trying to purify a sufficient dose of the cyclotide to test in mice.

Our paper detailing our discovery will soon appear online in the Journal of Natural Products.

Like Origami Paper, Proteins Must Be Folded Correctly

In Origami, 2-D pieces of paper can be folded into 3-D masterpieces. 

A protein is a linear sequence of amino acids linked together through peptide bonds. Proteins differ in the sequence of the twenty different amino acids that our cells assemble, and in their length. However, to function properly, the 1-D protein has to be correctly folded into a 3-D structure.

Hemoglobin (below) is the oxygen-carrying protein in our bloodstream, but it cannot carry oxygen unless its linear structure is folded properly. When a protein misfolds, it becomes toxic. Unlike other cells in the body, neurons cannot dilute the toxin by rapidly dividing. Misfolded proteins clog up transportation systems in neurons and cause them to die.

Each of the progressive neurodegenerative diseases is characterized by different proteins which misfold. Our strategy in developing new therapies for ALS, Alzheimer’s, and Parkinson’s is to find drugs that stop protein misfolding. We discovered that the amino acid L-serine helps to prevent protein misfolds.

Protein Misfolds Spread Like Prions in Alzheimer’s

The addition of L-serine to the diet of mice restored their memory

We believe protein misfolding to be the ultimate cause of Alzheimer’s, ALS, and other neurodegenerative diseases.

We discovered that environmental toxins such as BMAA can trigger protein misfolding.

How do protein misfolds spread from neuron to neuron? L-serine is produced within astrocytes, which help neurons.

Recently, a French team found that mice which cannot produce L-serine in astrocytes have memory problems. The addition of L-serine to their diet restored their memory.

Deficiencies in L-serine production within astrocytes may allow protein misfolds to propagate within the brain.

A New Approach to Parkinson’s Disease Therapy

David Long

Lewy bodies, formed from misfolded α-synuclein protein, are the neuropathological feature of Parkinson’s disease. While levodopa can help control symptoms, no current Parkinson’s medication slows disease progression.

 We attempted to produce Lewy bodies in vivo but did not have enough funds to continue the experiments. Enter Ty and Sue Measom of Logan, Utah, and Fred and Candy Berthrong of Providence, Utah who provided a generous gift to complete the study in which we found that BMAA triggers Lewy bodies in marmosets.

 We were unable to begin a second study until the philanthropic torch was picked up by Robert and Robin Paulson and Stan and Mary Seidler of Jackson Hole. They provided the lead gifts to determine if L-serine or L-tyrosine can slow Lewy body formation.

A generous pledge from David and Lisa Long of Lake Forest, Illinois allowed us to accelerate the project. Our colleagues at NeuroScience Associates in Tennessee assisted us by giving a significant discount on the regular fees for state-of-the-art sectioning and staining of the tissues. We still have $100,000 to raise to finish the project but are proceeding at full speed.

Because of the generous donors who helped us, including Bobbie Sweet, John Madigan, and James and Ellen Walton, we will have the final results in February 2022. If successful, this new drug will remain a lasting legacy for David Long who passed away on September 19, 2021.

Brain Chemistry Labs Welcome Dr. Samantha Gerlach to its Jackson Laboratories

Dr. Samantha Gerlach in Grand Teton National Park

An assistant professor at Dillard University in New Orleans, Dr. Gerlach joined the Brain Chemistry Labs team this summer to focus on active ingredients in native plants and their potential for new drug therapies for brain diseases, particularly glioblastoma.

 Brain Chemistry Labs’ Executive Director, Dr. Paul Alan Cox, and Dr. Gerlach both recognize the important connection of plants and their medicinal properties. In fact, Dr. Gerlach has spent a significant amount of time looking at violets.  She has hunted violets from Sweden to Samoa, not because of their beauty – which she admires – but because of their medicinal potential for new drugs.

 In her previous work, Dr. Gerlach learned that “violets produce a category of anti-cancer peptides known as cyclotides which in structure, resemble circular knotted or tangled puzzles.”

Dr. Gerlach goes on to explain that, “the anti-cancer activity is found in the knots, formed from linked sulfur molecules that give cyclotides a sharp point that can be used to puncture cancer cells. All too soon, cancer cells evolve resistance, so chemotherapy stops working. Cyclotides can punch pores into resistant breast cancer cells, restoring their susceptibility to chemotherapy."

Brain Chemistry Labs’ Executive Director Receives Prestigious Medal from the Garden Club of America

Dr. Paul Cox, Executive Director, Brain Chemistry Labs.

Dr. Paul Cox, Executive Director of the Brain Chemistry Labs, received one of the highest honors bestowed by The Garden Club of America (GCA), the Eloise Payne Luquer Medal for his scientific research related to ALS and Alzheimer’s disease. The medal was presented at the GCA’s annual meeting in Boston on May 19, 2019. According to GCA, “The Eloise Payne Luquer Medal is awarded for special achievement in the field of botany that may include medical research, the fine arts, or education and was presented with gratitude to a renowned ethnobotanist, consummate scientist, teacher, environmentalist, and activist, Dr. Paul Alan Cox. His compassion combined with his rigorous scientific methods are improving our world.”

GCA awards up to 10 National Medals a year to “nationally and internationally recognized leaders in their fields of study or achievement” and describes the medal winners as “visionaries all, passionate and influential, these men, women, and organizations have left a profound and lasting impact on the issues that are most important to the Garden Club of America.”

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Brain Chemistry Labs focus on Florida blooms.

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Dr. James Metcalf samples the waters of Florida

Massive cyanobacterial blooms associated with the emergency release of nutrient-laden Lake Okeechobee water down the St. Lucie river in the summer of 2016 exposed Florida residents to a potent toxin called microcystin which is known to cause liver cancer. READ MORE.

Brain Chemistry Labs' Movie Selected for Newport Beach Film Festival

It was a successful world premiere of the documentary Toxic Puzzle, featuring Brain Chemistry Labs’ Paul Alan Cox, his team in Jackson Hole and collaborators from around the world.

After the screening, the film’s director Bo Landin and Paul Cox answered questions in a Q&A. The film was also selected for the Earth Day Film Festival, and has been picked for review at the upcoming IMPACT Docs Awards.

Following the world premiere the film was broadcast in Sweden and Norway, attracting some 600,000 viewers and an interesting live online chat in Sweden and a very active ongoing discussion in social media inNorway. 

The film can now be streamed or downloaded from multiple online stores like Amazon, iTunes, Google, Microsoft and VUDU.

Dr. Paul Alan Cox Gives TED Talk at Jackson Hole

Paul Alan Cox is a Harvard Ph.D. who has searched for new medicines from plants used by traditional healers in the Pacific and Southeast Asia. For these efforts TIME magazine named him one of 11 "Heroes of Medicine." His efforts in preserving island rain forests were recognized with the Goldman Environmental Prize.