Accessible Requires Authentication Published by De Gruyter November 21, 2019

A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway

Thomas Berry, Eid Abohamza and Ahmed A. Moustafa

Abstract

High homocysteine levels in Alzheimer’s disease (AD) result from low activity of the trans-sulfuration pathway. Glutathione levels are also low in AD. L-cysteine is required for the synthesis of glutathione. The synthesis of coenzyme A (CoA) requires L-cysteine, which is synthesized via the trans-sulfuration pathway. CoA is required for the synthesis of acetylcholine and appropriate cholinergic neurotransmission. L-cysteine is required for the synthesis of molybdenum-containing proteins. Sulfite oxidase (SUOX), which is a molybdenum-containing protein, could be dysregulated in AD. SUOX detoxifies the sulfites. Glutaminergic neurotransmission could be dysregulated in AD due to low levels of SUOX and high levels of sulfites. L-cysteine provides sulfur for iron-sulfur clusters. Oxidative phosphorylation (OXPHOS) is heavily dependent on iron-sulfur proteins. The decrease in OXPHOS seen in AD could be due to dysregulations of the trans-sulfuration pathway. There is a decrease in aconitase 1 (ACO1) in AD. ACO1 is an iron-sulfur enzyme in the citric acid cycle that upon loss of an iron-sulfur cluster converts to iron regulatory protein 1 (IRP1). With the dysregulation of iron-sulfur cluster formation ACO1 will convert to IRP1 which will decrease the 2-oxglutarate synthesis dysregulating the citric acid cycle and also dysregulating iron metabolism. Selenomethionine is also metabolized by the trans-sulfuration pathway. With the low activity of the trans-sulfuration pathway in AD selenoproteins will be dysregulated in AD. Dysregulation of selenoproteins could lead to oxidant stress in AD. In this article, we propose a novel treatment for AD that addresses dysregulations resulting from low activity of the trans-sulfuration pathway and low L-cysteine.

References

Abdelazim, I.A., Abu-Faza, M., Shikanova, S., Zhurabekova, G., and Maghrabi, M.M. (2018). Heme-bound iron in treatment of pregnancy-associated iron deficiency anemia. J. Fam. Med. Prim. Care 7, 1434–1438. Search in Google Scholar

Achilli, C., Ciana, A., and Minetti, G. (2018). Brain, immune system and selenium: a starting point for a new diagnostic marker for Alzheimer’s disease? Perspect Public Health 138, 223–226. Search in Google Scholar

Ahn, C.S. (2009). Effect of taurine supplementation on plasma homocysteine levels of the middle-aged Korean women. Adv. Exp. Med. Biol. 643, 415–422. Search in Google Scholar

Akbaraly, T.N., Hininger-Favier, I., Carrière, I., Arnaud, J., Gourlet, V., Roussel, A.M., and Berr, C. (2007). Plasma selenium over time and cognitive decline in the elderly. Epidemiology 18, 52–58. Search in Google Scholar

Ali, A., Waly, M., Al-Farsi, Y.M., Essa, M.M., Al-Sharbati, M.M., and Deth, R.C. (2011). Hyperhomocysteinemia among Omani autistic children: a case-control study. Acta Biochim. Pol. 58, 547–551. Search in Google Scholar

Alzheimer’s Association. (2010). 2010 Alzheimer’s disease facts and figures. Alzheimers Dement. 6, 158–194. Search in Google Scholar

Alzheimer’s Association (2016). 2016 Alzheimer’s disease facts and figures. Alzheimers Dement. 12, 459–509. Search in Google Scholar

Anderson, S.A., Nizzi, C.P., Chang, Y.I., Deck, K.M., Schmidt, P.J., Galy, B., Damnernsawad, A., Broman, A.T., Kendziorski, C., Hentze, M.W., et al. (2013). The IRP1-HIF-2α axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab. 17, 282–290. Search in Google Scholar

Annerbo, S., Kivipelto, M., and Lokk, J. (2009). A prospective study on the development of Alzheimer’s disease with regard to thyroid-stimulating hormone and homocysteine. Dement. Geriatr. Cogn. Disord. 28, 275–280. Search in Google Scholar

Arimon, M., Takeda, S., Post, K.L., Svirsky, S., Hyman, B.T., and Berezovska, O. (2015). Oxidative stress and lipid peroxidation are upstream of amyloid pathology. Neurobiol. Dis. 84, 109–119. Search in Google Scholar

Baker, D.H. (2006). Comparative species utilization and toxicity of sulfur amino acids. J. Nutr. 136, 1670S–1675S. Search in Google Scholar

Barger, S.W., DeWall, K.M., Liu, L., Mrak, R.E., and Griffin, W.S. (2008). Relationships between expression of apolipoprotein E and beta-amyloid precursor protein are altered in proximity to Alzheimer beta-amyloid plaques: potential explanations from cell culture studies. J. Neuropathol. Exp. Neurol. 67, 773–783. Search in Google Scholar

Bermejo, P., Martín-Aragón, S., Benedí, J., Susín, C, Felici, E, Gil, P., Ribera, J.M., Villar, and A.M. (2008). Peripheral levels of glutathione and protein oxidation as markers in the development of Alzheimer’s disease from mild cognitive impairment. Free Radic. Res. 42, 162–170. Search in Google Scholar

Berr, C., Arnaud, J., and Akbaraly, T.N. (2012). Selenium and cognitive impairment: a brief-review based on results from the EVA study. Biofactors 38, 139–144. Search in Google Scholar

Bertram, L., McQueen, M.B., Mullin, K., Blacker, D., and Tanzi, R.E. (2007). Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat. Genet. 39, 17–23. Search in Google Scholar

Bianco, A.C. and Kim, BW. (2006). Deiodinases: implications of the local control of thyroid hormone action. J. Clin. Invest. 116, 2571–2591. Search in Google Scholar

Bochtler, M., Kolano, A., and Xu, G.L. (2017). DNA demethylation pathways: additional players and regulators. Bioessays 39, 1–13. Search in Google Scholar

Bridges, R.J., Natale, N.R., and Patel, S.A. (2012). System xc− cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br. J. Pharmacol. 165, 20–34. Search in Google Scholar

Brigelius-Flohé, R. and Maiorino, M. (2013). Glutathione peroxidases. Biochim. Biophys. Acta 1830, 3289–3303. Search in Google Scholar

Bubber, P., Haroutunian, V., Fisch, G., Blass, J.P., and Gibson, G.E. (2005). Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann. Neurol. 57, 695–703. Search in Google Scholar

Burk, R.F. and Hill, K.E. (2015). Regulation of selenium metabolism and transport. Annu. Rev. Nutr. 35, 109–134. Search in Google Scholar

Butler, J.D. and Zatz, M. (1984). Pantethine and cystamine deplete cystine from cystinotic fibroblasts via efflux of cysteamine-cysteine mixed disulfide. J. Clin. Invest. 74, 411–416. Search in Google Scholar

Butterfield, D.A. and Pocernich, C.B. (2003). The glutamatergic system and Alzheimer’s disease: therapeutic implications. CNS Drugs 17, 641–652. Search in Google Scholar

Calabrese, V., Sultana, R., Scapagnini, G., Guagliano, E., Sapienza, M., Bella, R., Kanski, J., Pennisi, G., Mancuso, C., Stella, A.M., et al. (2006). Nitrosative stress, cellular stress response, and thiol homeostasis in patients with Alzheimer’s disease. Antioxid. Redox. Signal 8, 1975–1986. Search in Google Scholar

Cardoso, S.M., Proença, M.T., Santos, S., Santana, I., and Oliveira, C.R. (2004). Cytochrome coxidase is decreased in Alzheimer’s disease platelets. Neurobiol. Aging 25, 105–110. Search in Google Scholar

Cardoso, B.R., Ong, T.P., Jacob-Filho, W., Jaluul, O., Freitas, M., and Cozzolino, S.M. (2010). Nutritional status of selenium in Alzheimer’s disease patients. Br. J. Nutr. 103, 803–806. Search in Google Scholar

Castellano, C., Cestari, V., and Ciamei, A. (2001). NMDA receptors and learning and memory processes. Curr. Drug Targets 2, 273–283. Search in Google Scholar

Chandrasekaran, K., Hatanpää, K., Brady, D.R., and Rapoport, S.I. (1996). Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer’s disease. Exp. Neurol. 142, 80–88. Search in Google Scholar

Cho, H.H., Cahill, C.M., Vanderburg, C.R., Scherzer, C.R., Wang, B., Huang, X., and Rogers, J.T. (2010). Selective translational control of the Alzheimer amyloid precursor proteintranscript by iron regulatory protein-1. J. Biol. Chem. 285, 31217. Search in Google Scholar

Chow, V.W., Mattson, M.P., Wong, P.C., and Gleichmann, M. (2010). An overview of APP processing enzymes and products. Neuromol. Med. 12, 1–12. Search in Google Scholar

Clarke, R., Smith, A.D., Jobst, K.A., Refsum, H., Sutton, L., and Ueland, P.M. (1998). Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch. Neurol. 55, 1449–1455. Search in Google Scholar

Cousins, R.J. (1983). Metallothionein-aspects related to copper and zinc metabolism. J. Inherit. Metab. Dis. 6, 15–21. Search in Google Scholar

Crespo, Â.C., Silva, B., Marques, L., Marcelino, E., Maruta, C., Costa, S., Timóteo, A., Vilares, A., Couto, F.S., Faustino, P., et al. (2014). Genetic and biochemical markers in patients with Alzheimer’s disease support a concerted systemic iron homeostasis dysregulation. Neurobiol. Aging 35, 777–785. Search in Google Scholar

Cummings, J.L., Morstorf, T., and Zhong, K. (2014). Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res. Ther. 6, 37. Search in Google Scholar

Cummings, J., Ritter, A., and Zhong, K. (2018). Clinical trials for disease-modifying therapies inAlzheimer’s disease: aprimer, lessons learned, and a blueprint for the future. J. Alzheimers Dis. 64, S3–S22. Search in Google Scholar

Cunningham, O., Gore, M.G., and Mantle, T.J. (2000). Initial-rate kinetics of the flavin reductase reaction catalyzed by human biliverdin-IXbeta reductase (BVR-B). Biochem. J. 345, 393–399. Search in Google Scholar

Di Giacomo, C., Latteri, F., Fichera, C., Sorrenti, V., Campisi, A., Castorina, C., Russo, A., Pinturo, R., and Vanella, A. (1993). Effect of acetyl-L-carnitine on lipid peroxidation and xanthine oxidase activity in rat skeletal muscle. Neurochem. Res. 18, 1157–1162. Search in Google Scholar

Di Santo, S.G., Prinelli, F., Adorni, F., Caltagirone, C., and Musicco, M. (2013). A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer’s disease. J. Alzheimers Dis. 35, 349–361. Search in Google Scholar

Doehner, W. and Landmesser, U. (2011). Xanthine oxidase and uric acid in cardiovasculardisease: clinical impact and therapeutic options. Semin. Nephrol. 31, 433–440. Search in Google Scholar

Drugs and Lactation Database (LactMed) [Internet]. (2006). Marine Oils. National Library of Medicine (US) (Bethesda, MD). Search in Google Scholar

Du, X., Li, H., Wang, Z., Qiu, S., Liu, Q., and Ni, J. (2013). Selenoprotein P and uric acid levels and Alzheimer’s selenoprotein Mblock Zn2+ -mediated Aβ42 aggregation and toxicity. Metallomics 5, 861–870. Search in Google Scholar

Du, X., Wang, C., and Liu, Q. (2016a). Potential roles of selenium and selenoproteins in the prevention of Alzheimer’s disease. Curr. Top. Med. Chem. 16, 835–848. Search in Google Scholar

Du, N., Xu, D., Hou, X., Song, X., Liu, C., Chen, Y., Wang, Y., and Li, X. (2016b). Inverse association between serum disease risk. Mol. Neurobiol. 53, 2594–2599. Search in Google Scholar

Eto, K., Asada, T., Arima, K., Makifuchi, T., and Kimura, H. (2002). Brain hydrogen sulfide is severely decreased in Alzheimer’s disease. Biochem. Biophys. Res. Commun. 293, 1485–1488. Search in Google Scholar

Farina, N., Jernerén, F., Turner, C., Hart, K., and Tabet, N. (2017). Homocysteine concentrations in the cognitive progression of Alzheimer’s disease. Exp. Gerontol. 99, 146–150. Search in Google Scholar

Ferreira-Vieira, T.H., Guimaraes, I.M., Silva, F.R., and Ribeiro, F.M. (2016). Alzheimer’s disease: targeting the cholinergic system. Curr. Neuropharmacol. 14, 101–115. Search in Google Scholar

Finley, E.B. and Cerklewski, F.L. (1983). Influence of ascorbic acid supplementation on copperstatus in young adult men. Am. J. Clin. Nutr. 37, 553–556. Search in Google Scholar

Frazer, D.M. and Anderson, G.J. (2014). The regulation of iron transport. Biofactors 40, 206–214. Search in Google Scholar

Fujii, S. (2004). ATP- and adenosine-mediated signaling in the central nervous system: the role of extracellular ATP in hippocampal long-term potentiation. J. Pharmacol. Sci. 94, 103–106. Search in Google Scholar

Galimberti, D. and Scarpini, E. (2011). Disease-modifying treatments for Alzheimer’s disease. Ther. Adv. Neurol. Disord. 4, 203–216. Search in Google Scholar

Gallucci, M., Zanardo, A., De Valentin, L., and Vianello, A. (2004). Homocysteine in Alzheimer disease and vascular dementia. Arch. Gerontol. Geriatr. Suppl. 9, 195–200. Search in Google Scholar

Gao, S., Jin, Y., Hall, K.S., Liang, C., Unverzagt, F.W., Ji, R., Murrell, J.R., Cao, J., Shen, J., Ma, F., et al. (2007). Selenium level and cognitive function in rural elderly Chinese. Am. J. Epidemiol. 165, 955–965. Search in Google Scholar

Giuliani, D., Ottani, A., Zaffe, D., Galantucci, M., Strinati, F., Lodi, R., and Guarini, S. (2013). Hydrogen sulfide slows down progression of experimental Alzheimer’s disease by targeting multiple pathophysiological mechanisms. Neurobiol. Learn. Mem. 104, 82–91. Search in Google Scholar

Gnandt, E., Dörner, K., Strampraad, M.F.J., de Vries, S., and Friedrich, T. (2016). The multitude of iron-sulfur clusters in respiratory complex I. Biochim. Biophys. Acta 1857, 1068–1072. Search in Google Scholar

González, S., Huerta, J.M., Alvarez-Uría, J., Fernández, S., Patterson, A.M., and Lasheras, C. (2004). Serum selenium is associated with plasma homocysteine concentrations in elderly humans. J. Nutr. 134, 1736–1740. Search in Google Scholar

Grey, V., Mohammed, S.R., Smountas, A.A., Bahlool, R., and Lands, L.C. (2003). Improved glutathione status in young adult patients with cystic fibrosis supplemented with whey protein. J. Cyst. Fibros. 2003 2, 195–198. Search in Google Scholar

Guerreiro, C., Silva, B., Crespo, Â.C., Marques, L., Costa, S., Timóteo, Â., Murrell, J.R., Cao, J., Shen, J., Ma, F., et al. (2015). Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer’s disease patients. Biochim. Biophys. Acta 1852, 2116–2122. Search in Google Scholar

Gwon, A.R., Park, J.S., Arumugam, T.V., Kwon, Y.K., Chan, S.L., Kim, S.H., Baik, S.-H., Yang, S., Yun, Y.-K., Choi, Y, et al. (2012). Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer’s disease. Aging Cell 11, 559–568. Search in Google Scholar

Haile, D.J., Rouault, T.A., Tang, C.K., Chin, J., Harford, J.B., and Klausner, R.D. (1992). Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster. Natl Acad. Sci. USA 89, 7536–7540. Search in Google Scholar

Han, D., Handelman, G., Marcocci, L., Sen, C.K., Roy, S., Kobuchi, H., Tritschler, H.J., Flohé, L., Packer, and L. (1997). Lipoic acidincreases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors 6, 321–338. Search in Google Scholar

Horn, D. and Barrientos, A. (2008). Mitochondrial copper metabolism and delivery to cytochrome c oxidase. IUBMB Life 60, 421–429. Search in Google Scholar

Hou, H. and Yu, H. (2010). Structural insights into histone lysine demethylation. Curr. Opin. Struct. Biol. 20, 739–748. Search in Google Scholar

Huntington Study Group Pre2CARE Investigators, Hyson, H.C., Kieburtz, K., Shoulson, I., McDermott, M., Ravina, B., de Blieck, E.A., de Blieck, E.A., Cudkowicz, M.E., Ferrante, R.J., Como, P., et al. (2010). Safety and tolerability of high-dosage coenzyme Q10 in Huntington’s disease and healthy subjects. Mov. Disord. 25, 1924–1928. Search in Google Scholar

Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. (1998). Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. (Washington, DC: National Academies Press). Search in Google Scholar

Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds. (2000). Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. (Washington, DC: National Academies Press). Search in Google Scholar

Institute of Medicine (US) Panel on Micronutrients. (2001). Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. (Washington, DC: National Academies Press). Search in Google Scholar

Iqbal, K., Liu, F., Gong, C.X., and Grundke-Iqbal, I. (2010). Tau in Alzheimer disease and related tauopathies. Curr. Alzheimer Res. 7, 656–664. Search in Google Scholar

Iwata, S., Lee, J.W., Okada, K., Lee, J.K., Iwata, M., Rasmussen, B., Link, T.A., Ramaswamy, S., Jap, and B.K. (1998). Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. Science 281, 64–71. Search in Google Scholar

Jabłońska, E. and Reszka, E. (2017). Selenium and epigenetics in cancer: focus on DNA methylation. Adv. Cancer. Res. 136, 193–234. Search in Google Scholar

Jeandel, C., Nicolas, M.B., Dubois, F., Nabet-Belleville, F., Penin, F., and Cuny, G. (1989). Lipid peroxidation and free radical scavengers in Alzheimer’s disease. Gerontology 35, 275–282. Search in Google Scholar

Jiang, R., Hua, C., Wan, Y., Jiang, B., Hu, H., Zheng, J., Fuqua, B.K., Dunaief, J.L., Anderson, G.J., David, S., et al. (2015). Hephaestin and ceruloplasmin play distinct but interrelated roles in iron homeostasis in mouse brain. J. Nutr. 145, 1003–1009. Search in Google Scholar

Johnson, M.K., Morningstar, J.E., Bennett, D.E., Ackrell, B.A., and Kearney, E.B. (1985). Magnetic circular dichroism studies of succinate dehydrogenase. Evidence for [2Fe-2S], [3Fe-xS], and [4Fe-4S] centers in reconstitutively active enzyme. J. Biol. Chem. 260, 7368–7378. Search in Google Scholar

Joosten, E., Lesaffre, E., Riezler, R., Ghekiere, V., Dereymaeker, L., Pelemans, W., and Dejaeger, E. (1997). Is metabolic evidence for vitamin B-12 and folate deficiency more frequent in elderly patients with Alzheimer’s disease? J. Gerontol. A. Biol. Sci. Med. Sci. 52, M76–M79. Search in Google Scholar

Jope, R.S. and Jenden, D.J. (1980). The utilization of choline and acetyl coenzyme A for the synthesis of acetylcholine. J. Neurochem. 35, 318–325. Search in Google Scholar

Kamat, P.K., Kyles, P., Kalani, A., and Tyagi, N. (2016). Hydrogen sulfide ameliorates homocysteine-induced Alzheimer’s disease-like pathology, blood-brain barrier disruption, and synaptic disorder. Mol. Neurobiol. 53, 2451–2467. Search in Google Scholar

Kappler, U. and Enemark, J.H. (2015). Sulfite-oxidizing enzymes. J. Biol. Inorg. Chem. 20, 253–264. Search in Google Scholar

Karakas, E., Wilson, H.L., Graf, T.N., Xiang, S., Jaramillo-Busquets, S., Rajagopalan, K.V., and Kisker, C. (2005). Structural insights into sulfite oxidase deficiency. J, Biol. Chem. 280, 33506–33515. Search in Google Scholar

Karimi, F., Borhani Haghighi, A., and Petramfar, P. (2011). Low levels of triiodothyronine in patients with Alzheimer’s disease. Iran J. Med. Sci. 36, 322–323. Search in Google Scholar

Kelley, E.E., Khoo, N.K., Hundley, N.J., Malik, U.Z., Freeman, B.A., and Tarpey, M.M. (2010). Hydrogen peroxide is the major oxidant product of xanthine oxidase. Free Radic. Biol. Med. 48, 493–498. Search in Google Scholar

Kim, H.Y., LaVaute, T., Iwai, K., Klausner, R.D., and Rouault, T.A. (1996). Identification of a conserved and functional iron-responsive element in the 5′-untranslated region of mammalian mitochondrial aconitase. J. Biol. Chem. 271, 24226–24230. Search in Google Scholar

Kim, S.H., Vlkolinsky, R., Cairns, N., Fountoulakis, M., and Lubec, G. (2001). The reduction of NADH ubiquinone oxidoreductase 24- and 75-kDa subunits in brains of patients with Down syndrome and Alzheimer’s disease. Life Sci. 68, 2741–2750. Search in Google Scholar

Kimura, H. (2011). Hydrogen sulfide: its production and functions. Exp. Physiol. 96, 833–835. Search in Google Scholar

Kitzlerová, E., Fisar, Z., Jirák, R., Zvĕrová, M., Hroudová, J., Benaková, H., and Raboch, J. (2014). Plasma homocysteine in Alzheimer’s disease with or without co-morbid depressivesymptoms. Neuro. Endocrinol. Lett. 35, 42–49. Search in Google Scholar

Klausner, R.D. and Rouault, T.A. (1993). A double life: cytosolic aconitase as a regulatory RNA binding protein. Mol. Biol. Cell 4, 1–5. Search in Google Scholar

Köhrle, J. (1999). Local activation and inactivation of thyroid hormones: the deiodinase family. Mol. Cell Endocrinol. 151, 103–119. Search in Google Scholar

Kumar, A. and Foster, T.C. (2019). Alteration in NMDA receptor mediated glutamatergic neurotransmission in the hippocampus during senescence. Neurochem. Res. 44, 38–48. Search in Google Scholar

Kweon, O.J., Youn, Y.C., Lim, Y.K., Lee, M.K., and Kim, H.R. (2019). Clinical utility of serum hepcidin and iron profile measurements in Alzheimer’s disease. J. Neurol. Sci. 403, 85–91. Search in Google Scholar

Laukka, T., Mariani, C.J., Ihantola, T., Cao, J.Z., Hokkanen, J., Kaelin, W.G. Jr., Godley, L.A., and Koivunen, P. (2016). Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 256–265. Search in Google Scholar

Leonardi, R. and Jackowski, S. (2007). Biosynthesis of pantothenic acid and coenzyme A. Eco. Sal. Plus 2, 2. Search in Google Scholar

Li, K., Tong, W.H., Hughes, R.M., and Rouault, T.A. (2006). Roles of the mammalian cytosoliccysteinedesulfurase, ISCS, and scaffold protein, ISCU, in iron-sulfur cluster assembly. J. Biol. Chem. 281, 12344–12351. Search in Google Scholar

Liao, Y., Xie, B., Zhang, H., He, Q., Guo, L., Subramaniapillai, M., Fan, B., Lu, C., Mclntyer, and R.S. (2019). Efficacy of omega-3 PUFAs in depression: a meta-analysis. Transl. Psychiatr. 9, 190. Search in Google Scholar

Licking, N., Murchison, C., Cholerton, B., Zabetian, C.P., Hu, S.C., Montine, T.J., Peterson-Hiller, A.L., Chung, K.A., Edwards, K., and Leverenz, J.B. (2017). Homocysteine and cognitive function in Parkinson’s disease. Parkinsonism Relat. Disord. 44, 1–5. Search in Google Scholar

Lim, S.C., Tajika, M., Shimura, M., Carey, K.T., Stroud, D.A.,Murayama, K., Ohtake, A., and McKenzie, M. (2018). Loss of the mitochondrial fatty acid β-oxidation protein medium-chain acyl-coenzyme adehydrogenase disrupts oxidative phosphorylation protein complex stability and function. Sci. Rep. 8, 153. Search in Google Scholar

Liu, X.B., Hill, P., and Haile, D.J. (2002). Role of the ferroportin iron-responsive element in ironandnitric oxide dependent gene regulation. Blood Cells Mol. Dis. 29, 315–326. Search in Google Scholar

Liu, X.Q., Jiang, P., Huang, H., and Yan, Y. (2008). Plasma levels of endogenous hydrogen sulfide and homocysteine in patients with Alzheimer’s disease and vascular dementia and the significance thereof. Zhonghua Yi Xue Za Zhi 88, 2246–2249. Search in Google Scholar

Lu, S.C. (2013). Glutathione synthesis. Biochim. Biophys. Acta 1830, 3143–3153. Search in Google Scholar

Lunnon, K., Keohane, A., Pidsley, R., Newhouse, S., Riddoch-Contreras, J., Thubron, E.B., Devall, M., Soininen, H., Kłoszewska, I., Mecocci, P., et al. (2017). Mitochondrial genes are altered in blood early in Alzheimer’s disease. Neurobiol. Aging 53, 36–47. Search in Google Scholar

Lyketsos, C.G., Steinberg, M., Tschanz, J.T., Norton, M.C., Steffens, D.C., and Breitner, J.C. (2000). Mental and behavioral disturbances in dementia: findings from the Cache County Study on memory in aging. Am. J. Psychiatr. 157, 708–714. Search in Google Scholar

Ma, F., Wu, T., Zhao, J., Ji, L., Song, A., Zhang, M., and Huang, G. (2017). Plasma homocysteine and serum folate and vitamin B12 levels in mild cognitive impairment and Alzheimer’s disease: a case-control study. Nutrients 9, E725. Search in Google Scholar

MacLeod, R.M., Farkas, W., Fridovich, I., and Handler, P. (1961). Purification and properties of hepatic sulfite oxidase. J. Biol. Chem. 236, 1841–1846. Search in Google Scholar

Maiuolo, J., Oppedisano, F., Gratteri, S., Muscoli, C., and Mollace, V. (2016). Regulation of uric acid metabolism and excretion. Int. J. Cardiol. 213, 8–14. Search in Google Scholar

Malenka, R.C. and Bear, M.F. (2004). LTP and LTD: an embarrassment of riches. Neuron 44, 5–21. Search in Google Scholar

Manczak, M., Park, B.S., Jung, Y., and Reddy, P.H. (2004). Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med. 5, 147–162. Search in Google Scholar

Mandal, P.K., Saharan, S., Tripathi, M., and Murari, G. (2015). Brain glutathione levels--a novel biomarker for mild cognitive impairment and Alzheimer’s disease. Biol. Psychiatr. 78, 702–710. Search in Google Scholar

Mangialasche, F., Baglioni, M., Cecchetti, R., Kivipelto, M., Ruggiero, C., Piobbico, D., Kussmaul, L., Monastero, R., Brancorsini, S., and Mecocci, P. (2015). Lymphocytic mitochondrial aconitase activity is reduced in Alzheimer’s disease and mild cognitive impairment. J. Alzheimers Dis. 44, 649–660. Search in Google Scholar

Marelja, Z., Stöcklein, W., Nimtz, M., and Leimkühler, S. (2008). A novel role for human Nfs1 inthecytoplasm: Nfs1 acts as a sulfur donor for MOCS3, a protein involved in molybdenum cofactor biosynthesis. J. Biol. Chem. 283, 25178–25185. Search in Google Scholar

Marelja, Z., Mullick Chowdhury, M., Dosche, C., Hille, C., Baumann, O., Löhmannsröben, H.G., and Leimkühler, S. (2013). The L-cysteine desulfurase NFS1 is localized in the cytosol where it provides the sulfur for molybdenum cofactor biosynthesis in humans. PLoS One 8, e60869. Search in Google Scholar

Marshall, J.R., Burk, R.F., Payne Ondracek, R., Hill, K.E., Perloff, M., Davis, W., Pili, R., George, S., Bergan, and R. (2017). Selenomethionine and methyl selenocysteine: multiple-dose pharmacokinetics inselenium-replete men. Oncotarget 8, 26312–26322. Search in Google Scholar

Mastrogiacoma, F., Lindsay, J.G., Bettendorff, L., Rice, J., and Kish, S.J. (1996). Brain protein and alpha-ketoglutarate dehydrogenase complex activity in Alzheimer’s disease. Ann. Neurol. 39, 592–598. Search in Google Scholar

McCaddon, A., Davies, G., Hudson, P., Tandy, S., and Cattell, H. (1998). Total serumhomocysteineinsenile dementia of Alzheimer type. Int. J. Geriatr. Psychiatr. 13, 235–239. Search in Google Scholar

McCaddon, A., Hudson, P., Davies, G., Hughes, A., Williams, J.H., and Wilkinson, C. (2001). Homocysteine and cognitive decline in healthy elderly. Dement. Geriatr. Cogn. Disord. 12, 309–313. Search in Google Scholar

McKinley, M.C. (2000). Nutritional aspects and possible pathological mechanisms of hyperhomocysteinaemia: an independent risk factor for vascular disease. Proc. Nutr. Soc. 59, 221–337. Search in Google Scholar

Medina, D., Thompson, H., Ganther, H., and Ip, C. (2001). Se-methylselenocysteine: a new compound for chemoprevention of breast cancer. Nutr. Cancer 40, 12–17. Search in Google Scholar

Mega, M.S., Cummings, J.L., Fiorello, T., and Gornbein, J. (1996). The spectrum of behavioral changes in Alzheimer’s disease. Neurology 46, 130–135. Search in Google Scholar

Mendel, R.R. (2015). The molybdenum cofactor. J. Biol. Chem. 288, 13165–13172. Search in Google Scholar

Mkrtchyan, G.V., Graf, A., Trofimova, L., Ksenofontov, A., Baratova, L., and Bunik, V. (2018). Positive correlation between rat brain glutamate concentrations and mitochondrial 2-oxoglutarate dehydrogenase activity. Anal. Biochem. 552, 100–109. Search in Google Scholar

Moustafa, A.A., Hewedi, D.H., Eissa, A.M., Frydecka, D., and Misiak, B. (2014). Homocysteinelevelsin schizophrenia and affective disorders-focus on cognition. Front. Behav. Neurosci. 8, 343. Search in Google Scholar

Moustafa, A.A., Hewedi, D.H., Eissa, A.M., Frydecka, D., and Misiak, B. (2015). Homocysteine levels in neurological disorders. Diet and Exercise in Cognitive Function and Neurological Diseases. T. Farooqui and A. Farooqui, eds. (Hoboken, NJ, USA: Wiley-Blackwell). Search in Google Scholar

Newcomer, J.W., Farber, N.B., and Olney, J.W. (2000). NMDA receptor function, memory, and brain aging. Dialogues Clin. Neurosci. 2, 219–232. Search in Google Scholar

Niciu, M.J., Kelmendi, B., and Sanacora, G. (2012). Overview of glutamatergic neurotransmission in the nervous system. Pharmacol. Biochem. Behav. 100, 656–664. Search in Google Scholar

Niu, Y., DesMarais, T.L., Tong, Z., Yao, Y., and Costa, M. (2015). Oxidative stress alters global histone modification and DNA methylation. Free. Radic. Biol. Med. 82, 22–28. Search in Google Scholar

Novoselov, S.V., Kim, H.Y., Hua, D., Lee, B.C., Astle, C.M., Harrison, D.E., Friguet, B., Moustafa, M.E., Carlson, B.A., Hatfield, D.L., et al. (2010). Regulation of selenoproteins and methionine sulfoxide reductases A and B1 by age, calorie restriction, and dietary selenium in mice. Antioxid. Redox. Signal. 12, 829–838. Search in Google Scholar

Ojha, R., Singh, J., Ojha, A., Singh, H., Sharma, S., and Nepali, K. (2017). An updated patent review: xanthine oxidase inhibitors for the treatment of hyperuricemia and gout (2011–2015). Expert Opin. Ther. Pat. 27, 311–345. Search in Google Scholar

Okuno, T., Ueno, H., and Nakamuro, K. (2006). Cystathionine gamma-lyase contributes toselenomethionine detoxification and cytosolic glutathione peroxidase biosynthesis inmouse liver. Biol. Trace Elem. Res. 109, 155–171. Search in Google Scholar

Oztürk, O.H., Küçükatay, V., Yönden, Z., Ağar, A., Bağci, H., and Delibaş, N. (2006). Expressions of N-methyl-D-aspartate receptors NR2A and NR2B subunit proteins in normal and sulfite-oxidase deficient rat’s hippocampus: effect of exogenous sulfite ingestion. Arch. Toxicol. 80, 671–679. Search in Google Scholar

Padurariu, M., Ciobica, A., Hritcu, L., Stoica, B., Bild, W., and Stefanescu, C. (2010). Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer’s disease. Neurosci. Lett. 469, 6–10. Search in Google Scholar

Pajonk, F.G., Kessler, H., Supprian, T., Hamzei, P., Bach, D., Schweickhardt, J., Herrmann, W., Obeid, R., Simons, A., Falkai, P., et al. (2005). Cognitive decline correlates with low plasma concentrations of copper in patients with mild to moderate Alzheimer’s disease. J. Alzheimers Dis. 8, 23–27. Search in Google Scholar

Pantopoulos, K. and Hentze, M.W. (1995). Rapid responses to oxidative stress mediated by ironregulatory protein. Rapid responses to oxidative stress mediated by iron regulatory protein. EMBO J. 14, 2917–2924. Search in Google Scholar

Papadia, C., Osowska, S., Cynober, L., and Forbes, A. (2018). Citrulline in health and disease. Review on human studies. Clin. Nutr. 37, 1823–1828. Search in Google Scholar

Parker, W.D. Jr., Filley, C.M., and Parks, J.K. (1990). Cytochrome oxidase deficiency in Alzheimer’s disease. Neurology 40, 1302–1303. Search in Google Scholar

Parmeggiani, B., Moura, A.P., Grings, M., Bumbel, A.P., de Moura Alvorcem, L., Tauana Pletsch, J., Fernandes, C.G., Wyse, A.T., Wajner, M., Leipnitz, G., et al. (2015). In vitro evidence that sulfite impairs glutamatergic neurotransmission and inhibits glutathione metabolism-related enzymes in rat cerebral cortex. Int. J. Dev. Neurosci. 42, 68–75. Search in Google Scholar

Pasiakos, S.M., McLellan, T.M., and Lieberman, H.R. (2015). The effects of protein supplements on muscle mass, strength, and aerobic and anaerobic power in healthy adults: a systematic review. Sports Med. 45, 111–131. Search in Google Scholar

Pourvali, K., Matak, P., Latunde-Dada, G.O., Solomou, S., Mastrogiannaki, M., Peyssonnaux, C., and Sharp, P.A. (2012). Basal expression of copper transporter 1 in intestinal epithelialcells is regulated by hypoxia-inducible factor 2α. FEBS Lett. 586, 2423–2427. Search in Google Scholar

Quinlan, P., Horvath, A., Wallin, A., and Svensson, J. (2019). Low serum concentration of free triiodothyronine (FT3) is associated with increased risk of Alzheimer’s disease. Psychoneuroendocrinology 99, 112–119. Search in Google Scholar

Raghuvanshi, R., Chandra, M., Misra, P.C., and Misra, M.K. (2005). Effect of vitamin E on the platelet xanthine oxidase and lipid peroxidation in the patients of myocardial infarction. Indian J. Clin. Biochem. 20, 26–29. Search in Google Scholar

Raha, A.A., Vaishnav, R.A., Friedland, R.P., Bomford, A., and Raha-Chowdhury, R. (2013). The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease. Acta Neuropathol. Commun. 1, 55. Search in Google Scholar

Rani, P., Krishnan, S., and Rani Cathrine, C. (2017). Study on analysis of peripheral biomarkers for Alzheimer’s disease diagnosis. Front. Neurol. 8, 328. Search in Google Scholar

Rasmussen, K.D. and Helin, K. (2016). Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 30, 733–750. Search in Google Scholar

Ravaglia, G., Forti, P., Maioli, F., Martelli, M., Servadei, L, Brunetti, N., Porcellini, E., and Licastro, F. (2005). Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am. J. Clin. Nutr. 82, 636–643. Search in Google Scholar

Riedel, G., Platt, B., and Micheau, J. (2003). Glutamate receptor function in learning and memory. Behav. Brain Res. 140, 1–47. Search in Google Scholar

Rinaldi, P., Polidori, M.C., Metastasio, A., Mariani, E., Mattioli, P., Cherubini, A., Catani, M., Cecchetti, R., Senin, U., Mecocci, P., et al. (2003). Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol. Aging 24, 915–919. Search in Google Scholar

Rogers, J.T., Randall, J.D., Cahill, C.M., Eder, P.S., Huang, X., Gunshin, H., Leiter, L., McPhee, J., Sarang, S.S., Utsuki, T., et al. (2002). An iron-responsive element type II in the 5′-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J. Biol. Chem. 277, 45518–45528. Search in Google Scholar

Rooseboom, M., Vermeulen, N.P., Groot, E.J., and Commandeur, J.N. (2002). Tissue distribution of cytosolic beta-elimination reactions of selenocysteine Se-conjugates in rat and human. Chem. Biol. Interact. 140, 243–264. Search in Google Scholar

Rouault, T.A. (2006). The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat. Chem. Biol. 2, 406–414. Search in Google Scholar

Rueli, R.H., Torres, D.J., Dewing, A.S., Kiyohara, A.C., Barayuga, S.M., Bellinger, M.T., Uyehara-Lock, J.H., White, L.R., Moreira, P.I., Berry, M.J., et al. (2017). Selenoprotein S reduces endoplasmic reticulum stress-induced phosphorylation of Tau: potential role in selenate mitigation of Tau pathology. J. Alzheimers Dis. 55, 749–762. Search in Google Scholar

Ryan, M.G., Ratnam, K., and Hille, R. (1995). The molybdenum centers of xanthine oxidase and xanthine dehydrogenase. Determination of the spectral change associated withreduction from the Mo(VI) to the Mo(IV) state. J. Biol. Chem. 270, 19209–19212. Search in Google Scholar

Salagre, E., Vizuete, A.F., Leite, M., Brownstein, D.J., McGuinness, A., Jacka, F., Dodd, S., Stubbs, B., Köhler, C.A., Vieta, E., et al. (2017). Homocysteine as a peripheral biomarker in bipolar disorder: a meta-analysis. Eur. Psychiatr. 43, 81–91. Search in Google Scholar

Sanchez, M., Galy, B., Schwanhaeusser, B., Blake, J., Bähr-Ivacevic, T., Benes, V., Benes, V., Selbach, M., Muckenthaler, M.U., and Hentze, M.W. (2011). Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins. Blood 118, e168–e179. Search in Google Scholar

Schirinzi, T., Di Lazzaro, G., Colona, V.L., Imbriani, P., Alwardat, M., Sancesario, G.M., Martorana, A., Pisani, and A. (2017). Assessment of serum uric acid as risk factor for tauopathies. J. Neural. Transm. (Vienna) 124, 1105–1108. Search in Google Scholar

Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosenberg, I.H., D’Agostino, R.B., Wilson, P.W., and Wolf, P.A. (2002). Plasmahomocysteine as a risk factor for dementia and Alzheimer’s disease. N. Engl. J. Med. 346, 476–483. Search in Google Scholar

Shah, Y.M., Matsubara, T., Ito, S., Yim, S.H., and Gonzalez, F.J. (2009). Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 9, 152–164. Search in Google Scholar

Shao, A. and Hathcock, J.N. (2008). Risk assessment for the amino acids taurine, L-glutamine and L-arginine. Regul. Toxicol. Pharmacol. 50, 376–399. Search in Google Scholar

Sharma, L.K., Lu, J., and Bai, Y. (2009). Mitochondrial respiratory complex I: structure, function and implication in human diseases. Curr. Med. Chem. 16, 1266–1277. Search in Google Scholar

Shi, L., Du, J.B., Pu, D.F., Qi, J.G., and Tang, C.S. (2006). Regulation of endogenous cystathionine- gamma-lyase gene expression in high pulmonary flow by nitric oxide precursor. Zhongguo Ying Yong Sheng Li Xue Za Zhi 22, 343–347. Search in Google Scholar

Snaedal, J., Kristinsson, J., Gunnarsdóttir, S., Olafsdóttir Baldvinsson, M., and Jóhannesson, T. (1998). Copper ceruloplasmin and superoxide dismutase in patients with Alzheimer’s disease: a case-control study. Dement. Geriatr. Cogn. Disord. 9, 239–242. Search in Google Scholar

Soda, K., Oikawa, T., and Esaki, N. (1999). Vitamin B6 enzymes participating in selenium aminoacid metabolism. Biofactors 10, 257–262. Search in Google Scholar

Speckmann, B. and Grune, T. (2015). Epigenetic effects of selenium and their implications for health. Epigenetics 10, 179–189. Search in Google Scholar

Sun, Q., Wang, B., Li, Y., Sun, F., Li, P., Xia, W., Zhou, X., Li, Q., Wang, X., Chen, J., Zeng, X., et al. (2016). Taurine supplementation lowers blood pressure and improves vascular function in prehypertension: randomized, double-blind, placebo-controlled study. Hypertension 67, 541–549. Search in Google Scholar

Suzuki, K., Iwata, A., and Iwatsubo, T. (2017). The past, present, and future of disease-modifying therapies for Alzheimer’s disease. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 93, 757–771. Search in Google Scholar

Szutowicz, A., Bielarczyk, H., Jankowska-Kulawy, A., Pawełczyk, T., and Ronowska, A. (2013). Acetyl-CoA the key factor for survival or death of cholinergic neurons in course of neurodegenerative diseases. Neurochem. Res. 38, 1523–1542. Search in Google Scholar

Szutowicz, A., Bielarczyk, H., Ronowska, A., Gul-Hinc, S., Klimaszewska-Łata, J., Dyś, A., Zyśk, M., and Pawełczyk, T. (2014). Intracellular redistribution of acetyl-CoA, the pivotal point in differential susceptibility of cholinergic neurons and glial cells to neurodegenerative signals. Biochem. Soc. Trans. 42, 1101–1106. Search in Google Scholar

Takano, N., Peng, Y.J., Kumar, G.K., Luo, W., Hu, H., Shimoda, L.A., Suematsu, M., Prabhakar, N.R., Semenza, and G.L. (2014). Hypoxia-inducible factors regulate human and rat cystathionine β-synthase gene expression. Biochem. J. 458, 203–211. Search in Google Scholar

Tamagno, E., Guglielmotto, M., Monteleone, D., and Tabaton, M. (2012). Amyloid-β production: major link between oxidative stress and BACE1. Neurotox. Res. 22, 208–219. Search in Google Scholar

Tarhonskaya, H., Nowak, R.P., Johansson, C., Szykowska, A., Tumber, A., Hancock, R.L., Lang, P., Flashman, E., Oppermann, U., Schofield, C.J., et al. (2017). Studies on the interaction of the histone demethylase KDM5B with tricarboxylic acid cycle intermediates. J. Mol. Biol. 429, 2895–2906. Search in Google Scholar

Taylor, M., Qu, A., Anderson, E.R., Matsubara, T., Martin, A., Gonzalez, F.J., and Shah, Y.M. (2011). Hypoxia-inducible factor-2α mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology 140, 2044–2055. Search in Google Scholar

Thomas, D.R., Hailwood, R., Harris, B., Williams, P.A., Scanlon, M.F., and John, R. (1987). Thyroid status in senile dementia of the Alzheimer type (SDAT). Acta Psychiatr. Scand. 76, 158–163. Search in Google Scholar

Tong, W.H. and Rouault, T.A. (2006). Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis. Cell Metab. 3, 199–210. Search in Google Scholar

Tsukada, Y., Fang, J., Erdjument-Bromage, H., Warren, M.E., Borchers, C.H., Tempst, P., and Zhang, Y. (2006). Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816. Search in Google Scholar

Tung, Y., Hsu, W.M., Wang, B.J., Wu, S.Y., Yen, C.T., Hu, M.K., and Liao, Y.F. (2008). Sodium selenite inhibits gamma-secretase activity through activation of ERK. Neurosci. Lett. 440, 38–43. Search in Google Scholar

van Eersel, J., Ke, Y.D., Liu, X., Delerue, F., Kril, J.J., Götz, J., and Ittner, L.M. (2010). Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer’s disease models. Proc. Natl Acad. Sci. USA 107, 13888–13893. Search in Google Scholar

Vural, H., Demirin, H., Kara, Y., Eren, I., and Delibas, N. (2010). Alterations of plasma magnesium, copper, zinc, iron and selenium concentrations and some related erythrocyte antioxidant enzyme activities in patients with Alzheimer’s disease. J. Trace Elem. Med. Biol. 24, 169–173. Search in Google Scholar

Walsh, D.M. and Teplow, D.B. (2012). Alzheimer’s disease and the amyloid β-protein. Prog. Mol. Biol. Transl. Sci. 107, 101–124. Search in Google Scholar

Wang, J. and Pantopoulos, K. (2011). Regulation of cellular iron metabolism. Biochem. J. 434, 365–381. Search in Google Scholar

Wang, X., Oberleas, D., Yang, M.T., and Yang, S.P. (1992). Molybdenum requirement of female rats. J. Nutr. 122, 1036–1041. Search in Google Scholar

Wang, Y., Mohsen, A.W., Mihalik, S.J., Goetzman, E.S., and Vockley, J. (2010). Evidence for physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes. J. Biol. Chem. 285, 29834–29841. Search in Google Scholar

Ward, D.M. and Kaplan, J. (2012). Ferroportin-mediated iron transport: expression and regulation. Biochim. Biophys. Acta 1823, 1426–1433. Search in Google Scholar

Watmough, N.J. and Frerman, F.E. (2010). The electron transfer flavoprotein: ubiquinone oxidoreductases. Biochim. Biophys. Acta 1797, 1910–1916. Search in Google Scholar

Weuve, J., Hebert, L.E., Scherr, P.A., and Evans, D.A. (2014). Deaths in the United States among persons with Alzheimer’s disease (2010-2050). Alzheimers Dement. 10, e40–e46. Search in Google Scholar

Whillier, S., Raftos, J.E., Chapman, B., and Kuchel, P.W. (2009). Role of N-acetylcysteine and cystine in glutathione synthesis in human erythrocytes. Redox Rep. 14, 115–124. Search in Google Scholar

Whitby, F.G., Phillips, J.D., Hill, C.P., McCoubrey, W., and Maines, M.D. (2002). Crystal structure of a biliverdin IX alpha reductase enzyme-cofactor complex. J. Mol. Biol. 319, 199–210. Search in Google Scholar

Willumsen, N., Vaagenes, H., Lie, O., Rustan, A.C, and Berge, R.K. (1999). Eicosapentaenoic and docosahexaenoic acid affect mitochondrial and peroxisomal fatty acid oxidation in relation to substrate preference. Lipids 34, 951–963. Search in Google Scholar

Wolff, N.A., Garrick, M.D., Zhao, L., Garrick, L.M., Ghio, A., and Thévenod, F. (2018). A role for divalent metal transporter (DMT1) in mitochondrial uptake of iron and manganese. Sci. Rep. 8, 211. Search in Google Scholar

Wong, B.X., Tsatsanis, A., Lim, L.Q., Adlard, P.A., Bush, A.I., and Duce, J.A. (2014). β-Amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin. PLoS One 9, e114174. Search in Google Scholar

Xie, L. and Collins, J.F. (2011). Transcriptional regulation of the Menkes copper ATPase (Atp7a) gene by hypoxia-inducible factor (HIF2{alpha}) in intestinal epithelial cells. Am. J. Physiol. Cell. Physiol. 300, C1298–C1305. Search in Google Scholar

Xie, Y., Tan, Y., Zheng, Y., Du, X., and Liu, Q. (2017). Ebselen ameliorates β-amyloid pathology, tau pathology, and cognitive impairment in triple-transgenic Alzheimer’s disease mice. J. Biol. Inorg. Chem. 22, 851–865. Search in Google Scholar

Xie, Y., Liu, Q., Zheng, L., Wang, B., Qu, X., Ni, J., Zhang, Y., and Du, X. (2018). Se-Methylselenocysteine ameliorates neuropathology and cognitive deficits by attenuating oxidative stress and metal dyshomeostasis in Alzheimer model mice. Mol. Nutr. Food Res. 62, e1800107. Search in Google Scholar

Xu, J., Church, S.J., Patassini, S., Begley, P., Waldvogel, H.J., Curtis, M.A., Faull, R.L.M., Unwin, R.D., and Cooper, G.J.S. (2017). Evidence for widespread, severe brain copper deficiency in Alzheimer’s dementia. Metallomics 9, 1106–1119. Search in Google Scholar

Xuan, A., Long, D., Li, J., Ji, W., Zhang, M., Hong, L., and Liu, J. (2012). Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in β-amyloid rat model of Alzheimer’s disease. J. Neuroinflamm. 9, 202. Search in Google Scholar

Yamori, Y., Liu, L., Mori, M., Sagara, M., Murakami, S., Nara, Y., and Mizushima, S. (2009). Taurine as the nutritional factor for the longevity of the Japanese revealed by a world-wide epidemiological survey. Adv. Exp. Med. Biol. 643, 13–25. Search in Google Scholar

Yamori, Y., Taguchi, T., Mori, H., and Mori, M. (2010). Low cardiovascular risks in the middleaged males and females excreting greater 24-hour urinary taurine and magnesium in 41 WHO-CARDIAC study populations in the world. J. Biomed. Sci. 17, S21. Search in Google Scholar

Yanfei, W., Lin, S., Junbao, D., and Chaoshu, T. (2006). Impact of L-arginine on hydrogensulfide/cystathionine-gamma-lyase pathway in rats with high blood flow-induced pulmonary hypertension. Biochem. Biophys. Res. Commun. 345, 851–857. Search in Google Scholar

Zhang, X., Vincent, A.S., Halliwell, B., and Wong, K.P. (2004). A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase. J. Biol. Chem. 279, 43035–43045. Search in Google Scholar

Zhang, C., Wang, R., Zhang, G., and Gong, D. (2016). Mechanistic insights into the inhibition of quercetin on xanthine oxidase. Int. J. Biol. Macromol. 112, 405–412. Search in Google Scholar

Zhao, Q.F., Tan, L., Wang, H.F., Jiang, T., Tan, M.S., Tan, L., Xu, W., Li, J.Q., Wang, J., Lai, T.J., et al. (2016). The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J. Affect. Disord. 190, 264–271. Search in Google Scholar

Zylberstein, D.E., Lissner, L., Björkelund, C., Mehlig, K., Thelle, D.S., Gustafson, D., Ostling, S., Waern, M., Guo, X., and Skoog, I. (2011). Midlife homocysteine and late-life dementia in women. A prospective population study. Neurobiol. Aging 32, 380–386. Search in Google Scholar

Received: 2019-08-09
Accepted: 2019-08-31
Published Online: 2019-11-21
Published in Print: 2020-04-28

©2020 Walter de Gruyter GmbH, Berlin/Boston