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Posts Tagged ‘one-carbon metabolism’


Late Onset of Alzheimer’s Disease and One-carbon Metabolism

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Abbreviations:

AD (Alzheimer’s disease)

amyloid-beta ()

late onset AD (LOAD)

GSK-3β (glycogen synthase kinase 3-beta)

PP2A (protein phosphatase 2A)

homocysteine (HCY)

S-adenosylmethionine (SAM)

methionine synthase (MS)

betaine-homocysteine methyltransferase (BHMT)

cystathionine beta synthase (CBS)

cysteine (Cys)

glutathione (GSH)

S-adenosylhomocysteine (SAH)

adenosine (Ado)

presenilin 1 (PSEN1)

beta-site APP cleaving enzyme 1 (BACE)

The two main molecular signs of AD are:

  • Extracellular deposits of Amyloid-beta (Aβ) peptides (amyloidogenic pathway) and
  • Intracellular deposits of phosphorylated protein TAU (fibrillogenic pathway)

For many years, both these two pathways (amyloidogenic and fibrillogenic) contended the role of “responsible” for AD onset in the researchers’ debates, even originating respectively the two groups of “BAptists” and “TAUists” scientists. In the recent years, however, these absolutist hypotheses were confuted by the emerging data evidencing that late onset AD (LOAD) has the characteristics to be considered a multifactorial disease and by scientific reports demonstrating possible interconnection between (but not limited to) the two above-mentioned “pathogenic” pathways.

For example, it was demonstrated that

  • GSK-3β (glycogen synthase kinase 3-beta), a phosphorylase involved in tau phosphorylation, is also responsible for APP (Amyloid Precursor Protein) phosphorylation and that
  • Aβ peptides are able to induce GSK-3β.

Among the several possible cocauses and interconnected pathways involved in LOAD onset and progression, a very rapidly emerging topic is related to the role of epigenetics. Moreover, it was hypothesized that methylation impairment could be a common promoter and/or a connection between amyloid and tau pathogenic pathways involving not only DNA methylation but also protein methylation mechanisms. This observation rises from studies on PP2A (protein phosphatase 2A) protein methylation showing that downregulation of neuronal PP2A methylation occurs in affected brain regions from AD patients, causing the accumulation of both phosphorylated tau and APP isoforms and increased secretion of Aβ peptides.

Altered methylation metabolism could represent the connection between B vitamins and LOAD. B vitamins are essential cofactors of homocysteine (HCY) metabolism, also called 1-carbon metabolism. One-carbon metabolism is a complex biochemical pathway regulated by the presence of folate, vitamin B12 and B6 (among other metabolites), and leading to the production of methyl donor molecule S-adenosylmethionine (SAM). High HCY and low B vitamin levels are associated to LOAD, even if a cause-effect relationship is still far to be ascertained; moreover, a clear correlation between HCY and Aβ levels has been found.

In addition, SAM, the principal metabolite in the HCY cycle and the main methyl donor in eukaryotes, appears to be altered in some neurological disorders, including AD. HCY, a thiol containing amino acid produced during the methionine metabolism via the adenosylated compound SAM, once formed is either converted to cysteine by transsulfuration or remethylated to form methionine. In the remethylation pathway HCY is remethylated by the vitamin B12-dependent enzyme methionine synthase (MS) using 5-methyltetrahydrofolate as cosubstrate. Alternatively, mainly in liver, betaine can donate a methyl group in a vitamin B12-independent reaction, catalyzed by betaine-homocysteine methyltransferase (BHMT). In the transsulfuration pathway, HCY can condense with serine to form cystathionine in a reaction catalyzed by the cystathionine beta synthase (CBS), a vitamin B6-dependent enzyme, and the cystathionine is hydrolyzed to cysteine (Cys). Cysteine is used for protein synthesis, metabolized to sulfate, or used for glutathione (GSH) synthesis. The tripeptide GSH is the most abundant intracellular nonprotein thiol, and it is a versatile reductant, serving multiple biological functions, acting, among others, as a quencher of free radicals and a cosubstrate in the enzymatic reduction of peroxides. HCY accumulation causes the accumulation of S-adenosylhomocysteine (SAH) because of the reversibility of the reaction converting SAH to HCY and adenosine (Ado); the equilibrium dynamic favors SAH synthesis. The reaction proceeds in the hydrolytic direction only if HCY and adenosine are efficiently removed. SAH is a strong DNA methyltransferases inhibitor, which reinforces DNA hypomethylation (Chiang et al., 1996). Thus, an alteration of the metabolism through either remethylation or transsulfuration pathways can lead to hyperhomocysteinemia, decrease of SAM/SAH ratio (methylation potential; MP), and alteration of GSH levels, suggesting that hypomethylation is a mechanism through which HCY is involved in vascular disease and AD, together with the oxidative damage. To add insult to injury, oxidative stress also promotes the formation of oxidized derivatives of HCY, like homocysteic acid and homocysteine sulfinic acid. These compounds, through the interaction with glutamate receptors, generate intracellular free radicals.

The first observations about B vitamins or HCY deficiency in neurological disorders were hypothesized in the 80 seconds. Despite this recent acknowledgement, alterations of HCY levels and related compounds were only recently widely recognized as risk factors for LOAD and other forms of dementia. Few mechanisms are suggested as possible protagonists in the toxic pathway of HCY in LOAD onset:

  • oxidative stress and neurotoxicity,
  • vascular damage,
  • alteration of cholesterol and lipids,
  • alteration of protein function by methylation and
  • deregulation of gene expression by DNA methylation.

These results were obtained by using both transgenic and dietary models of hyperhomocysteinemia or altered 1-carbon metabolism. On the one hand, this variety of experimental models allowed to investigate multiple aspects of the biochemical alterations and their consequences; on the other, the lacking of common methods or goals generated a large body of literature in part overlapping for some aspects but fragmentary or incomplete for others. This aspect represents, together with the scarce interplay between clinical/epidemiological and biomolecular research, one of the reasons for the poor relevance given by the scientific community to the role of 1-carbon metabolism in certain diseases like dementia.

A causal connection between 1-carbon alterations:

  • hyperhomocysteinemia,
  • low B vitamins,
  • low SAM, or
  • high SAH

and biological alterations responsible for LOAD onset and progression is still missing. So, it was previously demonstrated that 1-carbon metabolism was related to AD-like hallmarks (increased Aβ production) via PSEN1 (presenilin 1) and BACE (beta-site APP cleaving enzyme 1) upregulation in cellular and animal models. More recently, it was added to the rising literature body dealing with 1-carbon metabolism and GSK-3β and PP2A modulation; it was also demonstrated that PSEN1 promoter is regulated by site-specific DNA methylation in cell cultures and mice and that this modulation of methylation is dependent on the regulation of the DNA methylation machinery. Although all the proposed pathways of HCY toxicity are possibly involved and nonmutually exclusive, as suggested by the multifactorial origin of LOAD, the recent advances in the connection between epigenetics and LOAD (as discussed above) stress a primary role for methylation dishomeostasis dependent on 1-carbon metabolism alterations.

Source References:

http://www.sciencedirect.com/science/article/pii/S0197458011000741

http://www.sciencedirect.com/science/article/pii/0306987784901543

http://www.sciencedirect.com/science/article/pii/S1044743107002953

http://onlinelibrary.wiley.com/doi/10.1196/annals.1297.059/abstract;jsessionid=FE6A683C10230B201295DDF1388DAC68.d02t01

http://www.nejm.org/doi/full/10.1056/NEJMoa011613

Other articles related to this topic were published on this Open Access Online Scientific Journal, including the following:

Introduction to Nanotechnology and Alzheimer disease

Tilda Barliya PhD, RN 03/14/2013

https://pharmaceuticalintelligence.com/2013/03/14/introduction-to-nanotechnology-and-alzheimer-disease/

Alzheimer’s disease conundrum – Are we near the end of the puzzle?

Larry H Bernstein, MD, FCAP, RN 03/09/2013

https://pharmaceuticalintelligence.com/2013/03/09/alzheimers-disease-conundrum-are-we-near-the-end-of-the-puzzle/

Ustekinumab New Drug Therapy for Cognitive Decline resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

Aviva Lev-Ari, PhD, RN 02/27/2013

https://pharmaceuticalintelligence.com/2013/02/27/ustekinumab-new-drug-therapy-for-cognitive-decline-resulting-from-neuroinflammatory-cytokine-signaling-and-alzheimers-disease/

The Alzheimer Scene around the Web

Larry H Bernstein, MD, FCAP, Reporter, RN 11/02/2012

https://pharmaceuticalintelligence.com/2012/11/02/the-alzheimer-scene-around-the-web/

Alzheimer’s before Symptoms show: Imaging Techniques for Detection and Pre-Clinical Diagnosis

Aviva Lev-Ari, PhD, RN 09/29/2012

https://pharmaceuticalintelligence.com/2012/09/29/alzheimers-before-symptoms-show-imaging-techniques-for-detection-and-pre-clinical-diagnosis/

Blood markers for Alzheimer’s disease

Dr. Venkat S Karra, Ph.D., RN 09/05/2012

https://pharmaceuticalintelligence.com/2012/09/05/blood-markers-for-alzheimers-disease/

THREE new drugs for Alzheimer’s Disease: Two Antibodies against AMYLOID and one IV Immune Globulin

Aviva Lev-Ari, PhD, RN 07/17/2012

https://pharmaceuticalintelligence.com/2012/07/17/three-new-drugs-for-alzheimers-disease-two-antibodies-against-amyloid-and-one-iv-immune-globulin/

New ADNI Project to Perform Whole-genome Sequencing of Alzheimer’s Patients,

Aviva Lev-Ari, PhD, RN 07/03/2012

https://pharmaceuticalintelligence.com/2012/07/03/new-adni-project-to-perform-whole-genome-sequencing-of-alzheimers-patients/

New Bio-markers in Alzheimer’s & Stress Induced Changes in the Brains of Alzheimer’s Patients

Dr. Venkat S Karra, Ph.D., RN 06/26/2012

https://pharmaceuticalintelligence.com/2012/06/26/new-bio-markers-in-alzeihmers-stress-induced-changes-in-the-brains-of-alzheimers-patients/

 

How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

Larry H Bernstein, MD, FACP, RN 04/04/2013

https://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-and-hyperhomocusteinemia/

 

Problems of vegetarianism

Dr. Sudipta Saha, Ph.D., RN 04/22/2013

https://pharmaceuticalintelligence.com/2013/04/22/problems-of-vegetarianism/

 

Amyloidosis with Cardiomyopathy

Larry H Bernstein, MD, FACP, RN 03/31/2013

https://pharmaceuticalintelligence.com/2013/03/31/amyloidosis-with-cardiomyopathy/

 

Liver endoplasmic reticulum stress and hepatosteatosis

Larry H Bernstein, MD, FACP, RN 03/10/2013

https://pharmaceuticalintelligence.com/2013/03/10/liver-endoplasmic-reticulum-stress-and-hepatosteatosis/

 

Assessing Cardiovascular Disease with Biomarkers

Larry H Bernstein, MD, FACP, RN 12/25/2012

https://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/

 

Telling NO to Cardiac Risk

Stephen J. Williams, PhD, RN 12/10/2012

https://pharmaceuticalintelligence.com/2012/12/10/telling-no-to-cardiac-risk/

 

A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

Larry H Bernstein, MD, FACP, RN 12/03/2012

https://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/

 

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Larry H Bernstein, MD, FACP, RN 11/28/2012

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

 

The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

Larry H Bernstein, MD, FACP, RN 11/26/2012

https://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/

 

Nitric Oxide Function in Coagulation

Larry H Bernstein, MD, FACP, RN 11/26/2012

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/

 

The Potential for Nitric Oxide Donors in Renal Function Disorders

Larry H Bernstein, MD, FACP, RN 11/20/2012

https://pharmaceuticalintelligence.com/2012/11/20/the-potential-for-nitric-oxide-donors-in-renal-function-disorders/

 

Nitric Oxide, Platelets, Endothelium and Hemostasis

Larry H Bernstein, MD, FACP, RN 11/08/2012

https://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/

 

Expanding the Genetic Alphabet and linking the genome to the metabolome

Larry H Bernstein, MD, FACP, RN 09/24/2012

https://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-metabolome/

 

Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Larry H Bernstein, MD, FACP, RN 09/14/2012

https://pharmaceuticalintelligence.com/2012/09/14/interaction-of-nitric-oxide-and-prostacyclin-in-vascular-endothelium/

 

Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

Aviva Lev-Ari, PhD, RN 08/29/2012

https://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/

 

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

Larry H Bernstein, MD, FACP, RN 04/25/2013

https://pharmaceuticalintelligence.com/2013/04/25/contributions-to-vascular-biology/

 

Personalized Medicine in NSCLC

Larry H Bernstein, MD, FACP, RN 03/03/2013

https://pharmaceuticalintelligence.com/2013/03/03/personalized-medicine-in-nsclc/

 

Nitric Oxide and Immune Responses: Part 2

Aviral Vatsa PhD, MBBS, RN 10/28/2012

https://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

 

Mitochondrial Damage and Repair under Oxidative Stress

Larry H Bernstein, MD, FACP, RN 10/28/2012

https://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

 

Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Larry H Bernstein, MD, FACP, RN 10/17/2012

https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/

 

Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III

Larry H Bernstein, MD, FACP, RN 02/14/2012

https://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis-reconsidered/

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Larry H Bernstein, MD, FACP, RN 11/28/2012

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

Larry H Bernstein, MD, FACP, RN 11/26/2012

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/

New Insights on Nitric Oxide donors – Part IV

Larry H Bernstein, MD, FACP, RN 11/26/2012

https://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/

The Essential Role of Nitric Oxide and Therapeutic NO Donor Targets in Renal Pharmacotherapy

Larry H Bernstein, MD, FACP, RN 11/26/2012

https://pharmaceuticalintelligence.com/2012/11/26/the-essential-role-of-nitric-oxide-and-therapeutic-no-donor-targets-in-renal-pharmacotherapy/

Paclitaxel vs Abraxane (albumin-bound paclitaxel)

Tilda Barliya PhD, RN 11/17/2012

https://pharmaceuticalintelligence.com/2012/11/17/paclitaxel-vs-abraxane-albumin-bound-paclitaxel/

Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Larry H Bernstein, MD, FACP, RN 10/30/2012

https://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis/

Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

Larry H Bernstein, MD, FACP, RN 10/22/2012

https://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-of-therapeutic-targets/

Nitric Oxide and Immune Responses: Part 1

Aviral Vatsa PhD, MBBS, RN 10/18/2012

https://pharmaceuticalintelligence.com/2012/10/18/nitric-oxide-and-immune-responses-part-1/

Crucial role of Nitric Oxide in Cancer

Ritu Saxena, Ph.D., RN 10/16/2012

https://pharmaceuticalintelligence.com/2012/10/16/crucial-role-of-nitric-oxide-in-cancer/

Nitric Oxide Covalent Modifications: A Putative Therapeutic Target?

Stephen J. Williams, PhD, RN 09/24/2012

https://pharmaceuticalintelligence.com/2012/09/24/nitric-oxide-covalent-modifications-a-putative-therapeutic-target/

Nitric Oxide Signalling Pathways

Aviral Vatsa, PhD, MBBS, RN 08/22/2012

https://pharmaceuticalintelligence.com/2012/08/22/nitric-oxide-signalling-pathways/

Proteomics and Biomarker Discovery

Larry H Bernstein, MD, FACP, RN 08/21/2012

https://pharmaceuticalintelligence.com/2012/08/21/proteomics-and-biomarker-discovery/

The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure

Larry H Bernstein, MD, FACP, RN 08/20/2012

https://pharmaceuticalintelligence.com/2012/08/20/the-rationale-and-use-of-inhaled-no-in-pulmonary-artery-hypertension-and-right-sided-heart-failure/

Bystolic’s generic Nebivolol – positive effect on circulating Endothelial Progenitor Cells endogenous augmentation

Larry H Bernstein, MD, FACP, RN 07/16/2012

https://pharmaceuticalintelligence.com/2012/07/16/bystolics-generic-nebivolol-positive-effect-on-circulating-endothilial-progrnetor-cells-endogenous-augmentation/

The mechanism of action of the drug ‘Acthar’ for Systemic Lupus Erythematosus (SLE)

 Dr. Venkat S. Karra, Ph.D., RN 07/08/2012

https://pharmaceuticalintelligence.com/2012/07/08/the-mechanism-of-action-of-the-drug-acthar-for-systemic-lupus-erythematosus-sle/

Arthritis, Cancer: New Screening Technique Yields Elusive Compounds to Block Immune-Regulating Enzyme

Prabodh Kandala, PhD, RN 05/11/2012

https://pharmaceuticalintelligence.com/2012/05/11/arthritis-cancer-new-screening-technique-yields-elusive-compounds-to-block-immune-regulating-enzyme/

In Focus: Targeting of Cancer Stem Cells

Ritu Saxena, Ph.D, RN 03/27/2013

https://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

Novel Cancer Hypothesis Suggests Antioxidants Are Harmful

Ritu Saxena, Ph.D, RN 01/27/2013

https://pharmaceuticalintelligence.com/2013/01/27/novel-cancer-hypothesis-suggests-antioxidants-are-harmful/

What can we expect of tumor therapeutic response?

Larry H Bernstein, MD, FACP, RN 12/05/2012

https://pharmaceuticalintelligence.com/2012/12/05/what-can-we-expect-of-tumor-therapeutic-response/

Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Larry H Bernstein, MD, FACP, RN 09/16/2012

https://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/

Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

Ziv Raviv, PhD, RN 04/06/2013

https://pharmaceuticalintelligence.com/2013/04/06/targeting-mitochondrial-bound-hexokinase-for-cancer-therapy/

Genomics-based cure for diabetes on-the-way

Ritu Saxena, Ph.D, RN 03/04/2013

https://pharmaceuticalintelligence.com/2013/03/04/genomics-based-cure-for-diabetes-on-the-way/

PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack

Aviva Lev-Ari, PhD, RN 12/28/2012

https://pharmaceuticalintelligence.com/2012/12/28/plato-trial-on-acs-brilinta-ticagrelor-better-than-plavix-clopidogrel-bisulfate-lowering-chances-of-having-another-heart-attack/

Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I

Larry H Bernstein, MD, FACP, RN 11/26/2012

https://pharmaceuticalintelligence.com/2012/11/26/biochemistry-of-the-coagulation-cascade-and-platelet-aggregation/

Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation

Larry H Bernstein, MD, FACP, RN 09/26/2012

https://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-glycolysis-metabolic-adaptation/

Mitochondrial Mechanisms of Disease in Diabetes Mellitus

Aviva Lev-Ari, PhD, RN 08/01/2012

https://pharmaceuticalintelligence.com/2012/08/01/mitochondrial-mechanisms-of-disease-in-diabetes-mellitus/

Cardiovascular Disease (CVD) and the Role of Agent Alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Aviva Lev-Ari, PhD, RN 07/19/2012

https://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

Mitochondria: More than just the “powerhouse of the cell”

Ritu Saxena, Ph.D, RN 07/09/2012

https://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

Ovarian Cancer and fluorescence-guided surgery: A report

Tilda Barliya PhD, RN 01/19/2013

https://pharmaceuticalintelligence.com/2013/01/19/ovarian-cancer-and-fluorescence-guided-surgery-a-report/

NO Nutritional remedies for hypertension and atherosclerosis. It’s 12 am: do you know where your electrons are?

Meg Baker, Ph.D., Registered Patent Agent, RN 10/07/2012

https://pharmaceuticalintelligence.com/2012/10/07/no-nutritional-remedies-for-hypertension-and-atherosclerosis-its-12-am-do-you-know-where-your-electrons-are/

High Doses of Certain Dietary Supplements Increase Cancer Risk

Prabodh Kandala, PhD, RN 05/17/2012

https://pharmaceuticalintelligence.com/2012/05/17/high-doses-of-certain-dietary-supplements-increase-cancer-risk/

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