The homocysteine pathway: A new target for Alzheimer disease treatment?

Lao, José I.; Beyer, Katrin; Ariza, Aurelio

doi:10.1002/ddr.10360

Cited by 4 publications

(2 citation statements)

References 63 publications

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“…The ligating power of Hcys has been explored. Hcys is a biologically active thioamino acid, considered as the biomarker of oxidative stress which is also involved in cardiovascular disease, kidney failure, and other diseases. − The MB responses to Hg 2+ and Hcys have been analyzed on the basis of the proposed model of reversible MB interactions which enabled the determination of the conditional formation constant K THgT and the Gibbs free energy for T–Hg–T bridge formation. The model parameters, including the formation constants for Hcys complexes of Hg 2+ , have been determined from fluorimetric measurements of MB ON/OF switching and results of 1 H NMR spectral analysis.…”

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confidence: 99%

Mercury/Homocysteine Ligation-Induced ON/OFF-Switching of a T–T Mismatch-Based Oligonucleotide Molecular Beacon

Stobiecka¹,

Molinero²,

Chałupa³

et al. 2012

Anal. Chem.

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A molecular beacon (MB) with stem-loop (hairpin) DNA structure and with attached fluorophore-quencher pair at the ends of the strand has been applied to study the interactions of Hg(2+) ions with a thymine-thymine (T-T) mismatch in Watson-Crick base-pairs and the ligative disassembly of MB·Hg(2+) complex by Hg(2+) sequestration with small biomolecule ligands. In this work, a five base-pair stem with configuration 5'-GGTGG...CCTCC-3' for self-hybridization of MB has been utilized. In this configuration, the four GC base-pair binding energy is not sufficient to hybridize fully at intermediate temperatures and to form a hairpin MB conformation. The T-T mismatch built-in into the stem area can effectively bind Hg(2+) ions creating a bridge, T-Hg-T. We have found that the T-Hg-T bridge strongly enhances the ability of MB to hybridize, as evidenced by an unusually large MB melting temperature shift observed on bridge formation, ΔT(m) = +15.1 ± 0.5 °C, for 100 nM MB in MOPS buffer. The observed ΔT(m) is the largest of the ΔT(m) found for other MBs and dsDNA structures. By fitting the parameters of the proposed model of reversible MB interactions to the experimental data, we have determined the T-Hg-T bridge formation constant at 25 °C, K(1) = 8.92 ± 0.42 × 10(17) M(-1) from mercury(II) titration data and K(1) = 1.04 ± 0.51 × 10(18) M(-1) from the bridge disassembly data; ΔG° = -24.53 ± 0.13 kcal/mol. We have found that the biomarker of oxidative stress and cardiovascular disease, homocysteine (Hcys), can sequester Hg(2+) ions from the T-Hg-T complex and withdraw Hg(2+) ions from MB in the form of stable Hg(Hcys)(2)H(2) complexes. Both the model fitting and independent (1)H NMR results on the thymidine-Hg-Hcys system indicate also the high importance of 1:1 complexes. The high value of K(1) for T-Hg-T bridge formation enables analytical determinations of low concentrations of Hg(2+) (limit of detection LOD = 19 nM or 3.8 ppb, based on 3σ method) and Hcys (LOD = 23 nM, 3σ method). The conditional stability constants for Hg(Hcys)H(2)(2+) and Hg(Hcys)(2)H(2) at 52 °C have been determined, β(112) = 5.37 ± 0.3 × 10(46) M(-3), β(122) = 3.80 ± 0.6 × 10(68) M(-4), respectively.

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confidence: 99%

Mercury/Homocysteine Ligation-Induced ON/OFF-Switching of a T–T Mismatch-Based Oligonucleotide Molecular Beacon

Stobiecka¹,

Molinero²,

Chałupa³

et al. 2012

Anal. Chem.

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“…It has become clear that elevated levels of Hcy elicit neuronal death, including hippocampal and cortical neurons. 1,3 Cross-sectional magnetic resonance imaging (MRI) studies describe a similar correlation between high Hcy levels and cerebral atrophy. The increased level of tHcy predicts the rate of shrinkage of the medial temporal lobe in patients with AD.…”

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confidence: 97%

Therapeutic Cocktail Approach for Treatment of Hyperhomocysteinemia in Alzheimer’s Disease

et al. 2018

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In the United States, Alzheimer's disease (AD) is the most common cause of dementia, accompanied by substantial economic and emotional costs. During 2015, more than 15 million family members who provided care to AD patients had an estimated total cost of 221 billion dollars. Recent studies have shown that elevated total plasma levels of homocysteine (tHcy), a condition known as hyperhomocysteinemia (HHcy), is a risk factor for AD. HHcy is associated with cognitive decline, brain atrophy, and dementia; enhances the vulnerability of neurons to oxidative injury; and damages the blood–brain barrier. Many therapeutic supplements containing vitamin B12 and folate have been studied to help decrease tHcy to a certain degree. However, a therapeutic cocktail approach with 5-methyltetrahydrofolate, methyl B12, betaine, and N-acetylcysteine (NAC) have not been studied. This novel approach may help target multiple pathways simultaneously to decrease tHcy and its toxicity substantially.

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Evidence of Choline Depletion and Reduced Betaine and Dimethylglycine with Increased Homocysteine in Plasma of Children with Cystic Fibrosis

Innis

Hasman

2006

The Journal of Nutrition

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Cystic fibrosis (CF) is associated with many clinical complications including steatosis for which the relation to defective CF transmembrane conductance regulator protein is unclear. Choline deficiency results in hepatic steatosis. Choline is the precursor of betaine, which donates methyl groups for remethylation of homocysteine to methionine and dimethylglycine. Previously, we have shown phospholipid malabsorption and increased plasma homocysteine in children with CF. In these studies we used normal phase HPLC with tandem mass spectrometry to determine plasma choline, betaine, and dimethylglycine in children with CF (n = 34) and healthy control children without CF (n = 15). Plasma choline, betaine, and dimethylglycine were significantly lower in children with CF (means +/- SEM, 6.48 +/- 0.35, 23.8 +/- 1.49, 1.49 +/- 0.13 mumol/L, respectively) than in children without CF (8.98 +/- 0.46, 37.3 +/- 1.84, 3.01 +/- 0.17 mumol/L, respectively). Plasma choline (r = 0.373, P = 0.007) and betaine (r = 0.399, P = 0.005) were positively related to methionine, and choline was inversely related to homocysteine (r = -0.316, P = 0.03). Choline, betaine, and dimethylglycine were all significantly and positively related to the plasma S-adenosylmethionine:S-adenosylhomocysteine (SAM:SAH) ratio (r = 0.294, r = 0.377, r = 0.442, respectively; P < 0.05). The plasma choline:betaine and betaine:dimethylglycine ratios did not differ between the children with CF and the control children, suggesting no increase in betaine synthesis, or betaine-dependent remethylation of homocysteine. These studies suggest that choline depletion may contribute to increased homocysteine in children with CF. Choline depletion and altered thiol metabolism may contribute to the clinical complications associated with CF.

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The homocysteine pathway: A new target for Alzheimer disease treatment?

Cited by 4 publications

References 63 publications

Mercury/Homocysteine Ligation-Induced ON/OFF-Switching of a T–T Mismatch-Based Oligonucleotide Molecular Beacon

Mercury/Homocysteine Ligation-Induced ON/OFF-Switching of a T–T Mismatch-Based Oligonucleotide Molecular Beacon

Therapeutic Cocktail Approach for Treatment of Hyperhomocysteinemia in Alzheimer’s Disease

Evidence of Choline Depletion and Reduced Betaine and Dimethylglycine with Increased Homocysteine in Plasma of Children with Cystic Fibrosis

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