L-Serine, hope for Alzheimers and ALS

Misshapen proteins that collect in the brains of patients who eventually are diagnosed with Alzheimer’s dementia or in patients with ALS may be due to a substitution being made by BMAA a toxin in some types of cyanobacteria (a blue-green algae) in place of the amino acid L-serine.

Trials have begun with dietary intake of L-serine amino acid powder. The powder is readily available for purchase and is non toxic, (available online from bulk supplement companies that may market to weight lifters). Varying doses have been tried and 30 grams per day, slightly more than an ounce, have been found helpful. See: Alzheimer’s Disease – Could New Approach Lead to Breakthrough? (fortune.com).

The main researcher, Dr. Paul Cox, has a team or researchers involved now and has been focused on Alzheimer’s or ALS, however this is a breakthrough that might also help patients with autism as similar misshapen proteins are often found to be involved in that condition too. A review of research on levels of certain amino acid that have brain neurotransmitter roles in patients with autism diagnoses had some mixed results as there is a D-serine and L-serine form and levels of each can vary and whether a research study measured them separately of together was inconsistent, but several did find lower levels for patients with autism compared to the control group without an autism diagnosis.

See: Zheng HF, Wang WQ, Li XM, Rauw G, Baker GB. Body fluid levels of neuroactive amino acids in autism spectrum disorders: a review of the literature. Amino Acids. 2016;49(1):57-65. ncbi.nlm.nih.gov/PMC5241332/.

More recent research has not replicated or reinforced the theory that BMAA is involved in development of Alzheimer’s disease.

The role of the non-essential amino acid BMAA as a causal agent of Alzheimer’s or ALS may involve other factors in addition to chronic buildup of BMAA over time as a review of research about the topic did not conclude a causal relationship of the amino acid with neurodegenerative disorders.

  • See: A critical review of the postulated role of the non-essential amino acid, β-N-methylamino-L-alanine, in neurodegenerative disease in humans. Chernoff, et al, 2017, (ncbi.nlm.nih.gov).
  • Reanalysis of samples of the suspected source of BMAA from the initial research did not find significant amounts, see: The analysis of underivatized β-Methylamino-L-alanine (BMAA), BAMA, AEG & 2,4-DAB in Pteropus mariannus mariannus specimens using HILIC-LC-MS/MS. Foss et al, 2018, (ncbi.nlm.nih.gov).
  • β- N-Methylamino-l-alanine (BMAA) Not Involved in Alzheimer’s Disease. Rauk, 2018, (ncbi.nlm.nih.gov).

The prevailing theory that Beta amyloid protein is a causal agent in Alzheimer’s disease is now being questioned as almost 200 experimental drugs designed to decrease levels of the protein have been found ineffective as treatments for the disease. The protein is involved but likely isn’t the initial problem — regarding Beta amyloid in Alzheimer’s disease: “Brain amyloid is therefore generally accepted as being essential for disease progression but not sufficient on its own to drive disease. The next observable change in brain is impaired glucose metabolism within AD brain,” … “Based on these imaging and biomarker studies it is emerging that brain glucose
hypometabolism
(reduced glucose metabolism) and tau toxicity (increased phosphorylation of the Tau protein making it malfunction) likely reflect central events in the progression of AD (1,2,8).”  – Zhu et al, 2014, The emerging link between O-GlcNAc and Alzheimer’s disease, (jbc.org/content/early/2014/full.pdf)

So if BMAA is not a causal agent and Beta amyloid itself also isn’t the primary factor in development of Alzheimer’s disease – that leaves us asking what is involved? The answer is likely multifactorial – multiple issues that may vary somewhat for different patients.

Causal Agent versus Multifactorial Disorder.

Causal roles of a toxin traditionally look at toxins individually and as a toxin that would have the same risk for all people or animals if an animal study. Multifactorial disorders however may involve increased risk for some people based on genetic differences from average, or also require nutrient deficiencies to be present or other infectious or inflammatory conditions to also be present chronically.

Cyanotoxins including BMAA and a metabolite, DAB, have been analyzed for risk of cell death or inflammation in murine (aquatic rather than land based species) brain cells. Low doses of some of the cyanobacteria toxins were found to be a concern but not the BMAA or DAB.

  • See: Cyanotoxins at low doses induce apoptosis and inflammatory effects in murine brain cells: Potential implications for neurodegenerative diseases. Takser, et al, 2016 (ncbi.nlm.nih.gov).

The research by Dr. Paul Cox with BMAA in Alzheimer’s found that the risk association was with concentrated doses over decades,
(fortune.com), so lower doses may not be a significant risk or possibly risk may also require other factors to be present such as a chronically low intake of L-serine.

Many factors have been associated with increased risk for autism spectrum disorder some involving the early prenatal time of conception and implantation of the fetus and later stages of fetal development. Infants may seem to be developing typically and develop symptoms later as a toddler when rapid changes generally occur in the number of connections between brain cells. Genetic and environmental and nutrient deficiencies may also increase risk for the child later developing symptoms of autism or other cognitive conditions such as Attention Deficit/Hyperactive Disorder (ADHD).

  • For more information see: Causal Agent versus Multifactorial Disorder, which I am modifying into an easier to use format from a long series of posts on another of my sites, Believing is the First Step Towards Change.
  • An excerpt from that earlier document – Mice bred to be genetically defective in their ability to produce L-serine, a component of sphingolipids, all died as embryos – they never made it to birth. And: “As expected, all brain L-serine-derived lipids such as phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and GD3 ganglioside are greatly reduced in Phgdh knockout mice.” – See: Hirabayashi Y. A world of sphingolipids and glycolipids in the brain–novel functions of simple lipids modified with glucose. Proc Jpn Acad Ser B Phys Biol Sci. 2012;88(4):129-43.   ncbi.nlm.nih.gov/pmc/articles/PMC3406307/
  • Sphingolipid and serine synthesis are somewhat dependent on each other – inhibiting or increasing one or the other can inhibit or increase production of the other. This may help in treatment of cancer and help with better understanding of intellectual disability conditions as sphingolipid is important for a type of cell common to both. “Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness of aneuploid cells “– “Deciphering these mechanisms is important because aneuploidy is associated with diseases including intellectual disability and cancer.” — Hwang S, Gustafsson HT, O’Sullivan C, et al. Serine-Dependent Sphingolipid Synthesis Is a Metabolic Liability of Aneuploid CellsCell Rep. 2017;21(13):3807-3818. ncbi.nlm.nih.gov/pmc/articles/PMC5747309/

So is metabolic problems in serine metabolism or lack of protein in the diet an initial problem? or O-GlcNAc?

Serine is considered a non-essential amino acid because it can be made out of the amino acid glycine in normal health, or it can be converted back into glycine. (ScienceDirect/serine) Both glycine and serine are used in large amounts within myelin, the protein used to form the white fatty coating around the connecting channels between nerve cells. There are 18 molecules of serine within a molecule of myelin protein (172 amino acids long per an older source). See: Amino Acid Sequence of the Basic Protein of the Myelin Membrane, Eylar, 1970, (ncbi.nlm.nih.gov/page=3). – an old source but the graphic is viewable.

O-GlcNAc is a type of sugar/amino acid linkage that may have protective effects against Tau protein, another type of protein that seems to collect in the brain tissue of patients with Alzheimer’s disease. “O-GlcNAcylation is a dynamic form of protein glycosylation which involves the addition of β-d-N-acetylglucosamine (GlcNAc) via an O-linkage to serine or threonine residues of nuclear, cytoplasmic, mitochondrial and transmembrane proteins.” – Wani, et al, 2017, O-GlcNAcylation and neurodegeneration, (sciencedirect.com).

(*N-Acetylglucosamine is a type of monosaccharide that can be formed from a molecule of glucose in times of normal health. It is available as a supplement marketed for arthritis pain as glucosamine, generally derived from chitin found in shellfish. It is not typically found in common foods in the human diet.)(Health is a miracle of complex chemistry, in my opinion.)

Food Sources of L-Serine.

The research on BMAA and trials providing extra L-serine as a possible treatment for ALS (Amyotrophic lateral sclerosis, also known as Lou Gehrig’s Disease, a degenerative nerve condition which causes muscle paralysis) is discussed on another site in an article that includes a list of food sources of L-serine. Animal products such as dairy foods and a variety of meats are good sources but sesame, sunflower, and pumpkin and squash seeds are also sources along with hemp kernels, soy products and other beans, and peanuts and pistachio nuts. See: What is L-Serine and What is Research Telling Us? (naturalhealthyconcepts.com).

This very exciting as there is no shortage of L-serine, it is non-toxic commonly available in foods or as a bulk powder supplement, there would be no wait for a drug approval process. The clinical trials help prove efficacy, safety, and dosage recommendations.

Pumpkin seed kernels, raw, unsalted, with a standard size teaspoon.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Additional notes 2/19/2018:

  1. Suspected Link between ALS and Head Trauma (focus on sports trauma like soccer and football) https://www.sfchronicle.com/49ers/article/Suspected-link-between-ALS-and-head-trauma-11016025.php
  2. Links on brain injury and increased free glutamate https://www.google.com/search?q=brain+trauma+and+increassed+free+glutamate&rlz=1C1CHWA_enUS600US600&oq=brain+trauma+and+increassed+free+glutamate&aqs=chrome..69i57.10991j0j7&sourceid=chrome&ie=UTF-8
  3. L-Serine deficiency elicits intracellular accumulation of cytotoxic deoxy-sphingolipids and lipid body formation, when L-alanine and L-serine levels are out of balance, when an external source of L-serine is limited, sphingolipid production changes and
    1-deoxy-sphingolipids (doxSLs) are created http://www.jbc.org/content/early/2015/04/22/jbc.M114.603860
  4. Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction, “1-Deoxysphingolipids (deoxySLs) are atypical sphingolipids that are elevated in the plasma of patients with type 2 diabetes and hereditary sensory and autonomic neuropathy type 1 (HSAN1). Clinically, diabetic neuropathy and HSAN1 are very similar, suggesting the involvement of deoxySLs in the pathology of both diseases ” suspected mechanism of deoxySLs: “localized to mitochondria, causing mitochondrial fragmentation and dysfunction” which then may lead to neuropathy http://www.jlr.org/content/58/1/42.abstract

Actually we do know quite a bit about ALS

Rest in Peace, and condolences for families and friends of patients who died due to Amyotrophic Lateral Sclerosis (ALS).

This post was a follow up to: Amyotrophic Lateral Sclerosis (ALS) and CBD Receptors. transcendingsquare.com/2014/08/23/.

The Life Extension Foundation is a non-profit organization focused on research into preventative health strategies. The company does sell supplements, books, and a few other products but it also helps fund research in preventative health care. The foundation publishes an academic type journal and an article from the journal is available on their website which provides a review of the current theories and research available regarding Amyotrophic Lateral Sclerosis (ALS). [1]

The article ends with a quote or two about the limited effectiveness and negative side effects associated with the medication that is currently prescribed for ALS patients. The sad point is that at least then the doctor can feel like they provided a service by writing a prescription but if it doesn’t really help slow progress of the disease and adds negative side effects then is that prescribing doctor really “Doing no harm.“?

The article doesn’t provide vitamin or supplement recommendations or provide other preventative guidance. It is a review of current research which did provide enough information to suggest to me several strategies that might help me reduce my risk of developing ALS. I’m motivated because I fall into one of the ‘you may be at more risk for ALS if you also have this condition’ categories.

Studies suggest that ALS is more associated with some autoimmune and chronic infectious diseases and with some nutrient deficiencies or imbalances and with exposure to some environmental toxins.

A few points gleaned from the article that might help me reduce my risk of developing ALS:

  1. Avoid mercury, lead, aluminum, manganese and other heavy metal toxins.
  2. Be careful if working with herbicides and pesticides to reduce exposure.
  3. Have adequate intake of calcium and magnesium – in balance. Excess calcium and too little magnesium may increase degenerative calcification of the central nervous system.
  4. Avoid excess intake of free glutamates. There are many sources of free glutamates in the diet as they are used as flavoring agents. MSG is one better known example. *The article doesn’t recommend avoiding glutamates, it mentions that ALS is associated with glutamate toxicity. One study found plasma levels of glutamate to be significantly elevated in ALS patients compared to controls (Plaitakis et al, 1993). One theory suggests that there may be a glutamate transport problem that allows the elevated levels to accumulate. [1] *Having adequate zinc and magnesium levels helps the cells control intracellular glutamate levels. [3], magnesium also helps control transmembrane movement of the other electrolytes: calcium, sodium and potassium. [4]
    ALS is highly linked with glutamate. One proposed mechanism is a defective glutamate transport system that permits neurotoxic levels to build up (Onion 1998). A study showed significant elevations (by about 70%) of plasma levels of glutamate in ALS patients as compared to controls (Plaitakis et al. 1993). – See more at: http://www.lifeextensionvitamins.com/amlatscleral.html#sthash.ErWUopES.d
    ALS is highly linked with glutamate. One proposed mechanism is a defective glutamate transport system that permits neurotoxic levels to build up (Onion 1998). A study showed significant elevations (by about 70%) of plasma levels of glutamate in ALS patients as compared to controls (Plaitakis et al. 1993). – See more at: http://www.lifeextensionvitamins.com/amlatscleral.html#sthash.ErWUopES.dpuf
  5. Have adequate but not excessive intake of selenium as it helps the body remove mercury. Two Brazil nuts per day provide about 200 micrograms of selenium which is the recommended daily goal. Excess selenium can cause toxicity symptoms so be careful not to take supplemental one-a-day or other mixtures that contain selenium in addition to taking selenium as an individual supplement or in addition to eating Brazil nuts regularly. Toxicity wouldn’t occur in a few days but might develop if multiple sources were eaten over a longer time period.
  6. Growth factor deficiency may be involved in development of ALS. Touch is important for stimulating human growth factor. Therapy pets and massage may also help stimulate internal production of human growth factor. *The article doesn’t mention the therapeutic benefits of touch. It only mentions that reduced growth factors are an underlying problem associated with ALS and pharmaceutical sources have been found helpful for slowing progress of the disease in some (but not all) studies. However touch can also help stimulate innate production of growth factors without needing a pharmaceutical company. [2]
  7. Spinal compression may increase risks of a similar nerve degeneration problem that can resemble ALS so /speculative/ regular exercise such as swimming might help or regular use of an inversion board at a gentle 10 degree slope might help relieve spinal pressure. /Disclosure, I do use an inversion board and find it helpful for headache and back problems but they can be dangerous so please seek individual guidance regarding their use./
  8. Some infections with long term chronic phases are associated with ALS type symptoms including Lyme’s disease, poliomyelitis, HIV/AIDs, and tertiary syphilis.
  9. Some endocrine and autoimmune diseases such as the hyperthyroid condition Grave’s disease and  Diabetic Amyotrophy are associated with ALS risk. Maintaining lower thyroid levels and avoiding thyrotoxicosis may help reduce risk of developing ALS.
  10. Some other conditions associated with ALS like problems include the neurological diseases: Pick’s Disease and Kennedy’s Syndrome; and the genetic enzyme disorders: Superoxide Dismutase, Hexosaminidase A, and Alpha-Glucosidase.
  11. If you missed the previous post – adequate cannabinoids/phospholipids are an important factor in protecting against ALS. A list of legal food sources of cannabinoids or phospholipids is included, see: Amyotrophic Lateral Sclerosis (ALS) and CBD Receptors. transcendingsquare.com/2014/08/23/.
  1. Lyme disease and poliomyelitis
Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Scleros

/Disclaimer: This information is provided for educational purposes and is not intended to provide individual health guidance. Please see an health professional for individual health care purposes./

Amyotrophic Lateral Sclerosis (ALS) and CBD receptors

Addition, 7/30/2018 – ALS is a demyelination disorder. There is a 19% comordbidity rate with hyperthyroidism and ALS – so disclosure, not becoming paralyzed due to ALS is a personal goal of mine.  Legal sources of cannabinoids or some of the precursor building blocks – phospholipids or other phosphonutrients – include:

Hemp seed kernels and oil; Artemisia turanica/wormwood leaf; amaranth seed; asparagus; avocado fruit or the inner kernel, dried and powdered; beans/legumes; cardamom seeds and powder; carrots; celery stalks and leaves; cocoa beans and cocoa powder, baker’s chocolate, dark chocolate and to a lesser amount milk chocolate and chocolate syrup; coconut; cumin seed/powder; fennel seed, flax seed, pine nuts; sesame seeds, pumpkin seed kernels, squash seeds; butternut squash and pumpkin; gingko leaf; grapefruit and orange juice with the pulp; Jerusalem artichoke (this is a root vegetable rather than a green artichoke); lettuce, spinach and mustard leaves and other leafy green vegetables and herbs; nuts/peanuts, cashews, walnuts; oats; okra seeds; onion root, leek leaves, garlic;  parsnip root; pomegranate seeds and pomegranate peel extract;rice, white or brown but the bran is the best source; rosemary; sorghum;  sweet potato or yam; buckwheat (a seed botanically that is not wheat and is gluten free); wheat. (G.26)

Health – “the pursuit of life” is a right for United States citizens, and is included in the Preamble of the U.S. Constitution. (link)

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The cannabinoid receptor system is involved in the control of calcium movement across the cell membrane. Calcium has an electrically active ionic form which can initiate changes within the cell fluid. During normal health a similarly electrically active ionic form of magnesium is found in greater concentration within the cell fluid and greater concentrations of the calcium ion are found within the blood plasma. The energy available from the magnesium ions is used within the cell membrane protein channels. The protein transport channels act as gates that can be opened or closed to allow calcium or other types of chemicals to flow through the channel.

The US federal listing of the cannabis herb as a schedule one drug has limited research into the role of the cannabinoid receptor system to studies about the toxic or addictive properties of cannabinoids. A schedule one drug is considered as having no medicinal value so no research would be necessary. When the cannabis plant was classified as a schedule one substance less was known about the extensive role of cannabinoids in the health of humans and many other species. Suppressing research about the cannabinoid group of chemicals and the cannabinoid receptors may have left us in the dark about the cause and cure of many mystery diseases and conditions.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that affects a small percentage of the population yet it has no known cause or cure — except —  cannabinoids may help:

However, there is increasing evidence that cannabinoids and manipulation of the endocannabinoid system may have therapeutic value in ALS, in addition to other neurodegenerative conditions. Cannabinoids exert anti-glutamatergic and anti-inflammatory actions through activation of the CB(1) and CB(2) receptors, respectively. Activation of CB(1) receptors may therefore inhibit glutamate release from presynaptic nerve terminals and reduce the postsynaptic calcium influx in response to glutamate receptor stimulation. [1]

Other information:

Oxidative stress and Vitamin D deficiency or oxidation of the Vitamin D Binding Protein (DBP) may be involved in the development of ALS, (2), and Multiple sclerosis. Levels may continue to be low or oxidized during remission and worsen during relapse. (G12.33) There is a slightly modified form of the Vitamin D Binding Protein (GcMAF) that can promote  macrophages, immune system white blood cells, to remove cancer cells by apoptosis (killing and engulfing the cell debris to remove it from the body without causing toxic chemicals to be released into the extracellular fluid). (5)

The cannabinoid system may have some control over the system and it may have effects on other chronic conditions. I’m reading more on the topic.  – More health tips and conditions that may have an increased risk for ALS developing as a comorbid/additional condition are included in a follow up post: Actually we do know quite a bit about ALStranscendingsquare.com/2014/09/02/.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

    1. http://www.ncbi.nlm.nih.gov/pubmed/18781981
    2. Greilberger J, Greilberger M, Herwig R, (2017) Measurement of oxidative stress parameters, vitamin D and vitamin D binding protein during vitamin D treatment in a patient with amyotrophic lateral sclerosis. Integr Mol Med, 4: DOI: 10.15761/IMM.1000311
      http://www.oatext.com/measurement-of-oxidative-stress-parameters-vitamin-d-and-vitamin-d-binding-protein-during-vitamin-d-treatment-in-a-patient-with-amyotrophic-lateral-sclerosis.php
    3. Rajda C, Pukoli D, Bende Z, Majláth Z, Vécsei L. Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis. Kleinschnitz C, Meuth S, eds. International Journal of Molecular Sciences. 2017;18(2):353. doi:10.3390/ijms18020353. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343888/ (G12.33)
    4. Bíró T, Tóth BI, Haskó G, Paus R, Pacher P. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends in pharmacological sciences. 2009;30(8):411-420. doi:10.1016/j.tips.2009.05.004. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757311/ (4)
    5. Thyer, L.; Ward, E.; Smith, R.; Fiore, M.G.; Magherini, S.; Branca, J.J.V.; Morucci, G.; Gulisano, M.; Ruggiero, M.; Pacini, S. A Novel Role for a Major Component of the Vitamin D Axis: Vitamin D Binding Protein-Derived Macrophage Activating Factor Induces Human Breast Cancer Cell Apoptosis through Stimulation of MacrophagesNutrients 20135, 2577-2589. http://www.mdpi.com/2072-6643/5/7/2577/htm (5)
  1. Dario SiniscalcoJames J. BradstreetAlessandra Cirillo, Nicola Antonucci, 

    The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages. Journal of Neuroinflammation 2014 11:78   https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-11-78 (6)

  2. Bíró T, Tóth BI, Haskó G, Paus R, Pacher P. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends in pharmacological sciences. 2009;30(8):411-420. doi:10.1016/j.tips.2009.05.004. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757311/ (7)