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

Pomegranate Peel Extract – compilation of research

Around the world there are many teams working on uses of pomegranate peel for industrial, agricultural, food application, and human and veterinarian health care purposes. Much of it is organized in an initial draft along with links to some of my previous work on developing home recipes for personal use of pomegranate peel extract.

  • See: https://docs.google.com/document/d/1biWxjYHOHd-i73Wui69QIO6zVuqNwGHZdYU56H9pLTw/edit?usp=sharing
  • I will continue to work towards combining the previous information I’ve found and recipes and the new list of research references into one cohesive document, however in the interest of open research and advancing health and sustainability I’m sharing the initial draft now.
  • The health benefits have seemed like a miracle to me, sharing the good news in hope that it reaches more people is my goal.

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.

High blood pressure and possible ethnic differences

On page 66 of a new book Plagues and the Paradox of Progress: Why the World is Getting Healthier in Worrisome Ways, by Thomas Bollyky, it is mentioned that early Western medical personal working in Africa in the 1920s were surprised to find no cases of hypertension/high blood pressure among the native African people. Only one native woman was known to be overweight and it was noted that she worked in a brewery which led the medical person in the document to speculate whether beer drinking could be fattening (yes it can). The first case of hypertension in a native African person wasn’t noted until the 1940s.

Question: Does the Western style of living or working or export of Western products cause hypertension in native Africans? If native Africans living in their traditional environment using their traditional diet have no risk for hypertension then what changed that caused an increased risk? This topic is also important for prenatal health as preeclampsia can include hypertension/high blood pressure and it does tend to be an increased risk for women with African American ancestry. The DASH diet may be helpful, for more on preeclampsia risk factors and possible tips for prevention or management, see Preeclampsia & TRP Channelseffectivecare.info

Dr. Agbai’s discovery that helps protect against symptoms of Sickle Cell Anemia – Thiocyanate.

Yes per Dr Agbai who has worked with patients in Africa and in the U.S., the standard diets are different. There is a difference in type of starch and amount of starch in typical African or Jamaican diet and western U.S. style diet, and there is a difference in amounts of foods that contain thiocyanate. The yams commonly grown in Africa are larger and woodier/less sweet than sweet potatoes and they are also a good source of thiocyanate.

Thiocyanate is a phytonutrient that helps protect against Sickle cell anemia by preventing the red blood cells from forming the sickle shape instead of the normal round indented shape (like a tire or doughnut shape that has a filled in shallower center). It is important to eat adequate iodine and protein rich foods that contain methionine (found more in animal product protein sources than in a vegan diet) in order to protect thyroid health.

Listen to interviews with Dr. Agbai by the radio show Your Own Health and Fitness: http://www.yourownhealthandfitness.org/?page_id=509

Agbai O. Anti-sickling effect of dietary thiocyanate in prophylactic control of sickle cell anemia. J Natl Med Assoc. 1986;78(11):1053-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2571427/

There may be a slight difference in retention of calcium and loss of magnesium that would be protective with a diet low in calcium might may increase risk of metabolic syndrome type conditions when excess calcium.

I’ve discussed this topic of potential differences between western style diet and traditional African culture and possible differences in health in my early days of blogging when I found a research article from ~ 1970s that noted ethnic differences in health outcomes but did not take into account possible differences in average ethnic diet at the time. (I haven’t found that article in my files yet. I will update this post if I do find it.) To get to the point directly – people with native African ancestry may have kidney differences that conserve calcium better, and possibly not conserve as much magnesium, as other ethnic groups. This would be protective when calcium was not very available in the diet but then would be an increased negative health risk if the diet contained a lot of calcium or phosphorus.

There is known problems in medical research in the U.S. with bias in research studies towards use of white males as study participants with less information gathered about minority groups and females.

Before discussing calcium and magnesium and kidney health in more detail – briefly – there is bias in medical research towards white males. Research studies over the years have often had more limited numbers of minorities and females among the experimental and control groups or as a focus of research. A summary of the issue was included in a recent article in the New York Times that is focused on the potential benefits and risk of bias in the use of Artificial Intelligence (AI) in medical diagnostic processes or other medical roles.

” Medicine has long struggled to include enough women and minorities in research, despite knowing they have different risk factors for and manifestations of disease. Many genetic studies suffer from a dearth of black patients, leading to erroneous conclusions. Women often experience different symptoms when having a heart attack, causing delays in treatment. Perhaps the most widely used cardiovascular risk score, developed using data from mostly white patients, can be less precise for minorities. ” – Dhruv Khullar

“A.I. Could Worsen Health Disparities,” by Dhruv Khullar, The New York Times, Opinion, Jan. 31, 2019

It is not racist or sexist to discuss differences in physiology and the potential effects those differences might have on health. It is discriminatory to only study one group of people primarily and then try to treat everyone else as if they weren’t individuals but were all instead exactly like the group that had been studied. It is discrimination to not treat individuals as individuals or to pretend that differences don’t exist.

Adequate magnesium is needed for preventing high blood pressure, cardiovascular disease, and many other chronic conditions including dementia.

Low magnesium levels, particularly when there is also plenty of phosphorus may increase cardiovascular risks. Adequate magnesium levels are protective and elevated magnesium is unusual and may be increase cardiovascular risks. In good health the body maintains magnesium and other electrolyte levels within specific ranges. (5) Higher magnesium levels have also been associated with higher levels of potassium and of albumin, a blood plasma protein, (6), which is important for fluid balance and transport of a variety of chemicals in addition to magnesium (such as steroids, fatty acids, and thyroid hormones (wikipedia/serum albumin), about 30% of serum magnesium is carried in a non-electrically active form on proteins, primarily albumin (Clinical Biochemistry/serum magnesium) (9).

Alzheimer’s dementia and other types of dementia are more common in blacks than whites in the U.S. and may be a risk earlier in life too, early onset Alzheimer’s can occur in the forties and fifties instead of the more frequent age of diagnosis after age 60. See: African Americans Face Greater Risk of Alzheimer’s Disease than Whites, usatoday.. The reason is not known but the increased frequency on high blood pressure in blacks is thought to be a risk factor.

There may be differences in rate of urinary loss of albumin in different ethnic groups. With the presence of excess abdominal weight participants in a renal study of Hindustani-Surinamese, or African-Surinamese ancestry had an increased likelihood of albuminuria than participants of Dutch ancestry with the greatest risk found in the Hindustani-Surinamese group. (7) Asian Americans and African Americans were found to have better blood albumin levels in a renal study and the Asian Americans had better renal biomarkers compared to other ethnic groups in the study. (8)

When looking at hypertension and high blood pressure risk with the same diet in modern research there is a significant increased risk for African Americans to have high blood pressure and to have it occur earlier in life than in whites. (prevalence in the U.S. of hypertension in adults was “42 % for blacks and 28 % for whites,” (2011-2012)). (2)

So it is a good question – how did hypertension frequency in Africans in the 1920s change from zero to 42% for African Americans in the United States, in 2011-2012? Diet differences that were noted in 2009-2010 between white groups and African American groups were more cholesterol and sugar and less fiber, whole grains, nuts/beans/seeds, fruits and vegetables for the African Americans on average. Dairy intake was not mentioned as being significantly difference. In another research comparison calcium intake was lower on average in African Americans but so was magnesium (Table 1). (2)

Within the introduction and Diet and Blood Pressure sections of the article it is mentioned that ethnic differences in cardiovascular metabolism has been noted in African American groups and that their reduction in blood pressure when following the DASH diet was even better than the reduction in people of other ethnic background who followed the diet (it includes a magnesium rich Beans/Nuts/Seeds group as a daily/weekly recommendation). The INTERMAP study found an increased Sodium to Potassium ratio in urinary excretion and less total Potassium urinary excretion for the African American participants than white participants. (2)

Other research has also supported the idea that high blood pressure may have more to do with excess sodium (salt) intake in relation to low potassium intake than just having to do with the amount of sodium in the diet. Potassium is found in all vegetables and fruits in varying amounts, beans/nuts/seeds, and in liquid milk and yogurt. (Kidney dialysis and other patients with Chronic Kidney Disease have to avoid excess potassium so this article includes a list of potassium rich foods for the purpose of educating regarding what needs to be limited but for people of average kidney health it is a list of good sources to include in the diet: Potassium and Your CKD Diet, National Kidney Foundation.

Learning is an ongoing process, in the meantime some possible health tips for people of any ancestry:

  1. Adequate magnesium is essential for kidney and heart health and high blood pressure is an early symptom of low magnesium levels. Dietary sources may not be sufficient if intestinal absorption is poor or if renal losses are excessive. Epsom salt baths or footsoaks or magnesium chloride are topical forms. Adequate protein and phospholipids in the diet are also important to provide the albumin and other specialized transport molecules that carry magnesium and other chemicals within the vascular or other fluids of body tissue. More information about magnesium sources and symptoms of deficiency are available in a previous post: To have optimal Magnesium needs Protein and Phospholipids too.
  2. Adequate calcium and vitamin D are needed for health however excess may cause an imbalance between calcium and magnesium levels as magnesium is excreted along with excess calcium by the kidneys and less magnesium may be absorbed by the intestines as vitamin D causes increased absorption of calcium and magnesium but calcium may be more available in a modern processed food diet. For more information about vitamin D sources see: Light up your life with Vitamin D, peace-is-happy.org. Deficiency of calcium or of vitamin D can cause secondary hyperparathyroidism which can also be more common in renal failure due to excess phosphorus buildup and deficiency of active vitamin D. The healthy kidney is involved in activating vitamin D. (Secondary hyperparathyroidism, National Kidney Foundation) Calcium is plentiful in most dairy products and is also found in almonds, sesame seeds, beans, dark green leafy vegetables and other produce. Variations of a 2000 calorie menu plan shows that even a vegan diet can provide 1000 milligrams of calcium per day and a menu with dairy products can provide an excess with over 1600 milligrams of calcium, see: Healthy Hair is the Proof-of a healing diet.
  3. The DASH diet (Dietary Approach to Stop Hypertension) may help because it encourages potassium and magnesium rich vegetables, fruits, beans, nuts and seeds. Calcium is provided without being over recommended with two to three servings of dairy group foods. See example daily/weekly diet plan recommendations here: What is the DASH diet?, dashdiet.org.
  4. Adequate without excess protein helps protect the kidneys from having to overwork excreting nitrogen from excess protein breakdown. Adequate water is essential for kidney and vascular health as it helps with excretion of toxins and transport of nutrients and oxygen in the vascular system. More information about protein and water recommendations are available in a previous post: Make every day Kidney Appreciation Day.

/Disclaimer: This 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. Thomas Bollyky, Plagues and the Paradox of Progress: Why the World is Getting Healthier in Worrisome Ways, 2018, MIT Press, https://mitpress.mit.edu/books/plagues-and-paradox-progress
  2. Chan Q, Stamler J, Elliott P. Dietary factors and higher blood pressure in African-Americans. Curr Hypertens Rep. 2015;17(2):10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315875/“Marked ethnic differences exist in bone metabolism and development of calcified atherosclerotic plaque (CP). Relative to European-Americans, African-Americans have lower rates of osteoporosis (despite ingesting less dietary calcium), form fewer calcium-containing kidney stones and manifest skeletal resistance to PTH (1,2,3). Systemic differences in regulation of calcium and phosphorus appear to be involved (4). Related phenomena may include the markedly lower amounts of calcified CP in African-Americans, despite the presence of more severe conventional cardiovascular disease risk factors (5,6,7,8,9). Together these observations suggest biologically mediated ethnic differences in the regulation of bone and vascular health.” […]  “The DASH/DASH-Na diet BP reduction was more pronounced for blacks compared to whites [313637]. Although the DASH dietary approach has been incorporated into lifestyle changes recommended for patients with HTN [3], data show that few hypertensive Americans consume diets even modestly concordant with the DASH diet and less so for blacks [38]. Only about 19 % of individuals with known HTN from NHANES 1999–2004 had DASH-concordant diets.”
  3. Barry I. Freedman, et al, Vitamin D, Adiposity, and Calcified Atherosclerotic Plaque in African-Americans,J Clin Endocrinol Metab. 2010 March; 95(3): 1076–1083. [ncbi.nlm.nih.gov/pmc/articles/PMC2841532/?tool=pubmed]  
  4. Potassium and Your CKD Diet, National Kidney Foundation, https://www.kidney.org/atoz/content/potassium
  5. Ryota Ikee, Cardiovascular disease, mortality, and magnesium in chronic kidney disease: growing interest in magnesium-related interventions, Renal Replacement Therapy2018 4:1,   https://rrtjournal.biomedcentral.com/articles/10.1186/s41100-017-0142-7
  6. Noriaki Kurita, Tadao Akizawa, Masafumi Fukagawa, Yoshihiro Onishi, Kiyoshi Kurokawa, Shunichi Fukuhara; Contribution of dysregulated serum magnesium to mortality in hemodialysis patients with secondary hyperparathyroidism: a 3-year cohort study, Clinical Kidney Journal, Volume 8, Issue 6, 1 December 2015, Pages 744–752, https://doi.org/10.1093/ckj/sfv097
  7. van Valkengoed IG, Agyemang C, Krediet RT, Stronks K. Ethnic differences in the association between waist-to-height ratio and albumin-creatinine ratio: the observational SUNSET study. BMC Nephrol. 2012;13:26. Published 2012 May 7. doi:10.1186/1471-2369-13-26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492102/
  8. Frankenfield DL, et al., Differences in intermediate outcomes for Asian and non-Asian adult hemodialysis patients in the United States, Kidney International, Vol 64, Issue 2, Aug. 2003, pp 623-631 https://www.sciencedirect.com/science/article/pii/S0085253815493706
  9. M H Kroll, R J Elin, Relationships between magnesium and protein concentrations in serum. Clinical Chemistry Feb 1985, 31 (2) 244-246; http://clinchem.aaccjnls.org/content/31/2/244.long