Dr. Ron’s Research Review – July 3, 2019

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This week’s research review focuses on L-serine for neuroprotection

In human neuroblastoma cell cultures, non-human primates and human beings, L-serine is neuroprotective. Although L-serine is generally classified as a non-essential amino acid, it is probably more appropriate to term it as a "conditional non-essential amino acid" since, under certain circumstances vertebrates cannot synthesize it in sufficient quantities to meet necessary cellular demands. L-serine is biosynthesized in the mammalian central nervous system from 3-phosphoglycerate and serves as a precursor for the synthesis of the amino acids glycine and cysteine. Physiologically, it has a variety of roles, perhaps most importantly as a phosphorylation site in proteins. Mutations in the metabolic enzymes that synthesize L-serine have been implicated in various human diseases. Dosing of animals with L-serine and human clinical trials investigating the therapeutic effects of L-serine support the FDA's determination that L-serine is generally regarded as safe (GRAS); it also appears to be neuroprotective. (Metcalf et al., 2018)
Ogimi village in Okinawa is renowned for its aging population. The most frequently consumed food items, including tofu and seaweeds, are rich in the dietary amino acid l-serine. l-serine content of the Ogimi diet >8 grams/day for Ogimi women significantly exceeds the average American dietary intake of 2.5 grams/day for women >70 years old. The authors hypothesize that the high l-serine content of the Ogimi diet is related to the paucity of tangle diseases among villagers is buttressed by in vivo results with non-human primates where dietary l-serine slowed development of neurofibrillary tangles and β-amyloid plaques by up to 85% and a human clinical trial finding that l-serine at 15 grams/day twice daily slows functional decline in ALS patients. (Cox and Metcalf, 2017)
L-serine is converted into either D-serine or pyruvate ammonia for elimination.
A recent study showed that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between non-demented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis. (Madeira et al., 2015)
A recent study showed that chronic d-serine supplementation impairs insulin secretion. Chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. (Suwandhi et al., 2018)

Dr. Ron


 

Articles

Traditional Food Items in Ogimi, Okinawa: l-Serine Content and the Potential for Neuroprotection.
            (Cox and Metcalf, 2017) Download
PURPOSE OF REVIEW:  Ogimi village is renowned for its aging population. We sought to determine if the l-serine content of their diet could account for their neurological health. RECENT FINDINGS:  The most frequently consumed food items, including tofu and seaweeds, are rich in the dietary amino acid l-serine. l-serine content of the Ogimi diet >8 grams/day for Ogimi women significantly exceeds the average American dietary intake of 2.5 grams/day for women >70 years old. Our hypothesis that the high l-serine content of the Ogimi diet is related to the paucity of tangle diseases among villagers is buttressed by in vivo results with non-human primates where dietary l-serine slowed development of neurofibrillary tangles and β-amyloid plaques by up to 85% and a human clinical trial finding that l-serine at 15 grams/day twice daily slows functional decline in ALS patients. Analysis of the Ogimi diet suggests that l-serine should be evaluated for therapeutic potential as a neuroprotective agent.

d-serine levels in Alzheimer's disease: implications for novel biomarker development.
            (Madeira et al., 2015) Download
Alzheimer's disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.

L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential.
            (Metcalf et al., 2018) Download
In human neuroblastoma cell cultures, non-human primates and human beings, L-serine is neuroprotective, acting through a variety of biochemical and molecular mechanisms. Although L-serine is generally classified as a non-essential amino acid, it is probably more appropriate to term it as a "conditional non-essential amino acid" since, under certain circumstances, vertebrates cannot synthesize it in sufficient quantities to meet necessary cellular demands. L-serine is biosynthesized in the mammalian central nervous system from 3-phosphoglycerate and serves as a precursor for the synthesis of the amino acids glycine and cysteine. Physiologically, it has a variety of roles, perhaps most importantly as a phosphorylation site in proteins. Mutations in the metabolic enzymes that synthesize L-serine have been implicated in various human diseases. Dosing of animals with L-serine and human clinical trials investigating the therapeutic effects of L-serine support the FDA's determination that L-serine is generally regarded as safe (GRAS); it also appears to be neuroprotective. We here consider the role of L-serine in neurological disorders and its potential as a therapeutic agent.

Chronic d-serine supplementation impairs insulin secretion.
            (Suwandhi et al., 2018) Download
OBJECTIVE:  The metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis. METHODS:  We apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals. RESULTS:  We show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans. CONCLUSION:  Thus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.

 

 

References

Cox, PA and JS Metcalf (2017), ‘Traditional Food Items in Ogimi, Okinawa: l-Serine Content and the Potential for Neuroprotection.’, Curr Nutr Rep, 6 (1), 24-31. PubMed: 28331770
Madeira, C, et al. (2015), ‘d-serine levels in Alzheimer’s disease: implications for novel biomarker development.’, Transl Psychiatry, 5 e561. PubMed: 25942042
Metcalf, JS, et al. (2018), ‘L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential.’, Neurotox Res, 33 (1), 213-21. PubMed: 28929385
Suwandhi, L, et al. (2018), ‘Chronic d-serine supplementation impairs insulin secretion.’, Mol Metab, 16 191-202. PubMed: 30093356