Abstract
Mercury (Hg), which is a non-essential element, is considered a highly toxic pollutant for biological systems even when present at trace levels. Elevated Hg exposure with the growing release of atmospheric pollutant Hg and rising accumulations of mono-methylmercury (highly neurotoxic) in seafood products have increased its toxic potential for humans. This review aims to highlight the potential relationship between Hg exposure and Alzheimer’s disease (AD), based on the existing literature in the field. Recent reports have hypothesized that Hg exposure could increase the potential risk of developing AD. Also, AD is known as a complex neurological disorder with increased amounts of both extracellular neuritic plaques and intracellular neurofibrillary tangles, which may also be related to lifestyle and genetic variables. Research reports on AD and relationships between Hg and AD indicate that neurotransmitters such as serotonin, acetylcholine, dopamine, norepinephrine, and glutamate are dysregulated in patients with AD. Many researchers have suggested that AD patients should be evaluated for Hg exposure and toxicity. Some authors suggest further exploration of the Hg concentrations in AD patients. Dysfunctional signaling pathways in AD and Hg exposure appear to be interlinked with some driving factors such as arachidonic acid, homocysteine, dehydroepiandrosterone (DHEA) sulfate, hydrogen peroxide, glucosamine glycans, glutathione, acetyl-L carnitine, melatonin, and HDL. This evidence suggests the need for a better understanding of the relationship between AD and Hg exposure, and potential mechanisms underlying the effects of Hg exposure on regional brain functions. Also, further studies evaluating brain functions are needed to explore the long-term effects of subclinical and untreated Hg toxicity on the brain function of AD patients.
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References
Aaseth J, Alexander J, Bjørklund G, Hestad K, Dusek P, Roos PM, Alehagen U (2016) Treatment strategies in Alzheimer’s disease: a review with focus on selenium supplementation. Biometals 29:827–839. https://doi.org/10.1007/s10534-016-9959-8
Abram Z, Korossy S (1994) Presynaptic and postsynaptic effects of mercuric ions on Guinea-pig ileum longitudinal muscle strip preparation. Neurochem Res 19:1467–1472. https://doi.org/10.1007/BF00968992
Aguado A, Galán M, Zhenyukh O, Wiggers GA, Roque FR, Redondo S, Peçanha F, Martín A, Fortuño A, Cachofeiro V (2013) Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways. Toxicol Appl Pharmacol 268:188–200. https://doi.org/10.1016/j.taap.2013.01.030
Alattia J-R, Kuraishi T, Dimitrov M, Chang I, Lemaitre B, Fraering PC (2011) Mercury is a direct and potent γ-secretase inhibitor affecting notch processing and development in drosophila. FASEB J 25:2287–2295. https://doi.org/10.1096/fj.10-174078
Alexandrov PN, Pogue AI, Lukiw WJ (2018) Synergism in aluminum and mercury neurotoxicity. Integr Food Nutr Metab 5(3). https://doi.org/10.15761/IFNM.1000214
Alimonti A, Ristori G, Giubilei F, Stazi MA, Pino A, Visconti A, Brescianini S, Sepe Monti M, Forte G, Stanzione P, Bocca B, Bomboi G, D’Ippolito C, Annibali V, Salvetti M, Sancesario G (2007) Serum chemical elements and oxidative status in Alzheimer’s disease, Parkinson disease and multiple sclerosis. Neurotoxicology 28:450–456. https://doi.org/10.1016/j.neuro.2006.12.001
Alkadhi KA, Dao AT (2018) Exercise decreases BACE and APP levels in the hippocampus of a rat model of Alzheimer's disease. Mol Cell Neurosci 86:25–29. https://doi.org/10.1016/j.mcn.2017.11.008
Allen JW, Mutkus LA, Aschner M (2001) Mercuric chloride, but not methylmercury, inhibits glutamine synthetase activity in primary cultures of cortical astrocytes. Brain Res 891:148–157. https://doi.org/10.1016/S0006-8993(00)03185-1
Ally A, Buist R, Mills P, Reuhl K (1993) Effects of methylmercury and trimethyltin on cardiac, platelet, and aorta eicosanoid biosynthesis and platelet serotonin release. Pharmacol Biochem Behav 44:555–563. https://doi.org/10.1016/0091-3057(93)90166-Q
Alzheimer A (1906) Uber einen eigenartigen schweren Er Krankungsprozeb der Hirnrinde. Neurologisches Centralblatt 23:1129–1136
Arnhold F, Gührs K-H, von Mikecz A (2015) Amyloid domains in the cell nucleus controlled by nucleoskeletal protein Lamin B1 reveal a new pathway of mercury neurotoxicity. PeerJ 3:e754. https://doi.org/10.7717/peerj.754
Arrifano GPF, de Oliveira MA, Souza-Monteiro JR, Paraense RSO, Ribeiro-dos-Santos A, dos Santos Vieira JR, da Costa Silva AL, da Silva FM, de Matos MB (2018) Role for apolipoprotein e in neurodegeneration and mercury intoxication. Front Biosci (elite edition) 10:229–241. https://doi.org/10.2741/e819
Aschner M, Yao CP, Allen JW, Tan KH (2000) Methylmercury alters glutamate transport in astrocytes. Neurochem Int 37:199–206. https://doi.org/10.1016/S0197-0186(00)00023-1
Aschner M, Syversen T, Souza D, JBTd R, Farina M (2007) Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity. Braz J Med Biol Res 40:285–291. https://doi.org/10.1590/S0100-879X2007000300001
Ballester F, Iñiguez C, Murcia M, Guxens M, Basterretxea M, Rebagliato M, Vioque J, Lertxundi A, Fernandez-Somoano A, Tardon A (2018) Prenatal exposure to mercury and longitudinally assessed fetal growth: relation and effect modifiers. Environ Res 160:97–106. https://doi.org/10.1016/j.envres.2017.09.018
Baraldi M, Zanoli P, Tascedda F, Blom JM, Brunello N (2002) Cognitive deficits and changes in gene expression of NMDA receptors after prenatal methylmercury exposure. Environ Health Perspect 110:855. https://doi.org/10.1289/ehp.02110s5855
Basu N, Stamler CJ, Loua KM, Chan HM (2005) An interspecies comparison of mercury inhibition on muscarinic acetylcholine receptor binding in the cerebral cortex and cerebellum. Toxicol Appl Pharmacol 205:71–76. https://doi.org/10.1016/j.taap.2004.09.009
Basu N, Kwan M, Man Chan H (2006) Mercury but not organochlorines inhibits muscarinic cholinergic receptor binding in the cerebrum of ringed seals (Phoca hispida). J Toxicol Environ Health A 69:1133–1143. https://doi.org/10.1080/15287390500362394
Basu N, Clarke E, Green A, Calys-Tagoe B, Chan L, Dzodzomenyo M, Fobil J, Long RN, Neitzel RL, Obiri S (2015) Integrated assessment of artisanal and small-scale gold mining in Ghana—part 1: human health review. Int J Environ Res Public Health 12:5143–5176. https://doi.org/10.3390/ijerph120505143
Basun H, Forssell L, Wetterberg L, Winblad B (1991) Metals and trace elements in plasma and cerebrospinal fluid in normal aging and Alzheimer’s disease. J Neural Transm Park Dis Dement Sect 3:231–258
Bavec Š, Gosar M, Miler M, Biester H (2017) Geochemical investigation of potentially harmful elements in household dust from a mercury-contaminated site, the town of Idrija (Slovenia). Environ Geochem Health 39:443–465. https://doi.org/10.1007/s10653-016-9819-z
Bedir Findik R, Celik HT, Ersoy AO, Tasci Y, Moraloglu O, Karakaya J (2016) Mercury concentration in maternal serum, cord blood, and placenta in patients with amalgam dental fillings: effects on fetal biometric measurements. J Matern Fetal Neonatal Med 29:3665–3669. https://doi.org/10.3109/14767058.2016.1140737
Bencko V, Wagner V, Wagnerova M, Ondrejcak V (1990) Immunological profiles in workers occupationally exposed to inorganic mercury. J Hyg Epidemiol Microbiol Immunol 34:9–15
Benhamú B, Martín-Fontecha M, Vázquez-Villa H, Pardo L, Lopez-Rodriguez ML (2014) Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer’s disease. J Med Chem 57:7160–7181
Berr C, Balansard B, Arnaud J, Roussel AM, Alperovitch A (2000) Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement Arteriel J Am Geriatr Soc 48:1285–1291. https://doi.org/10.1111/j.1532-5415.2000.tb02603.x
Bjørklund G (1991) Mercury as a potential source for the etiology of Alzheimer’s disease. Trace Elem Med 8:208–208
Bjørklund G (2015) Selenium as an antidote in the treatment of mercury intoxication. Biometals 28:605–614. https://doi.org/10.1007/s10534-015-9857-5
Bjørklund G, Dadar M, Mutter J, Aaseth J (2017a) The toxicology of mercury: current research and emerging trends. Environ Res 159:545–554. https://doi.org/10.1016/j.envres.2017.08.051
Bjørklund G, Aaseth J, Ajsuvakova OP, Nikonorov AA, Skalny AV, Skalnaya MG, Tinkov AA (2017b) Molecular interaction between mercury and selenium in neurotoxicity. Coord Chem Rev 332:30–37. https://doi.org/10.1016/j.ccr.2016.10.009
Bjørklund G, Mutter J, Aaseth J (2017c) Metal chelators and neurotoxicity: lead, mercury, and arsenic. Arch Toxicol 91:3787-3797. https://doi.org/10.1007/s00204-017-2100-0
Bjørklund G, Bengtsson U, Chirumbolo S, Kern JK (2017d) Concerns about environmental mercury toxicity: do we forget something else? Environ Res 152:514–516. https://doi.org/10.1016/j.envres.2016.08.038
Bjørklund G, Chirumbolo S, Geier DA, Kern JK, Geier MR (2017e) Histone deacetylase inhibitors, thimerosal, and autism spectrum disorder. Environ Res 156:843–844. https://doi.org/10.1016/j.envres.2017.04.007
Bjørklund G, Lindh U, Aaseth J, Mutter J, Chirumbolo S (2019) Mercury in dental amalgams: a great concern for clinical toxicology in developing countries? J Trace Elem Med Biol 51:9–11. https://doi.org/10.1016/j.jtemb.2018.09.002
Black FJ, Bokhutlo T, Somoxa A, Maethamako M, Modisaemang O, Kemosedile T, Cobb-Adams C, Mosepele K, Chimbari M (2011) The tropical African mercury anomaly: lower than expected mercury concentrations in fish and human hair. Sci Total Environ 409:1967–1975. https://doi.org/10.1016/j.scitotenv.2010.11.027
Black P, Richard M, Rossin R, Telmer K (2017) Assessing occupational mercury exposures and behaviours of artisanal and small-scale gold miners in Burkina Faso using passive mercury vapour badges. Environ Res 152:462–469. https://doi.org/10.1016/j.envres.2016.06.004
Bodienkova G, Boklazhenko E (2017) Relationship between cytokine concentrations and the level of antibodies to neuronal proteins as dependent on the severity of mercury neurotoxicity. Hum Physiol 43:334–338. https://doi.org/10.1134/S0362119717020037
Bourgade K, Garneau H, Giroux G, Le Page AY, Bocti C, Dupuis G, Frost EH, Fülöp T (2015) β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology 16:85–98. https://doi.org/10.1007/s10522-014-9538-8
Bradley-Whitman MA, Lovell MA (2015) Biomarkers of lipid peroxidation in Alzheimer disease (AD): an update. Archives of Toxicology 89(7):1035–1044
Bourgade K, Le Page A, Bocti C, Witkowski JM, Dupuis G, Frost EH, Fülöp T Jr (2016) Protective effect of amyloid-β peptides against herpes simplex virus-1 infection in a neuronal cell culture model. J Alzheimers Dis 50:1227–1241. https://doi.org/10.3233/JAD-150652
Breteler MM, Claus JJ, van Duijn CM, Launer LJ, Hofman A (1992) Epidemiology of Alzheimer’s disease. Epidemiol Rev 14:59–82. https://doi.org/10.1093/oxfordjournals.epirev.a036092
Brouwers N, Van Cauwenberghe C, Engelborghs S, Lambert J, Bettens K, Le Bastard N, Pasquier F, Montoya AG, Peeters K, Mattheijssens M (2012) Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Mol Psychiatry 17:223. https://doi.org/10.1038/mp.2011.24
Burk RF, Hill KE (2009) Selenoprotein P-expression, functions, and roles in mammals. Biochim Biophys Acta 1790:1441–1447. https://doi.org/10.1016/j.bbagen.2009.03.026
Cai Z, Hussain MD, Yan L-J (2014) Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int J Neurosci 124:307–321. https://doi.org/10.3109/00207454.2013.833510
Caito SW, Milatovic D, Hill KE, Aschner M, Burk RF, Valentine WM (2011) Progression of neurodegeneration and morphologic changes in the brains of juvenile mice with selenoprotein P deleted. Brain Res 1398:1–12. https://doi.org/10.1016/j.brainres.2011.04.046
Calabrese EJ, Baldwin LA (2003) Toxicology rethinks its central belief. Nature 421:691. https://doi.org/10.1038/421691a
Calabrese EJ, Iavicoli I, Calabrese V, Cory-Slechta DA, Giordano J (2018) Elemental mercury neurotoxicity and clinical recovery of function: a review of findings, and implications for occupational health. Environ Res 163:134–148. https://doi.org/10.1016/j.envres.2018.01.021
Cao B, Lv W, Jin S, Tang J, Wang S, Zhao H, Guo H, Su J, Cao X (2013) Degeneration of peripheral nervous system in rats experimentally induced by methylmercury intoxication. Neurol Sci 34:663–669. https://doi.org/10.1007/s10072-012-1100-3
Cassano T, Pace L, Bedse G, Michele Lavecchia A, De Marco F, Gaetani S, Serviddio G (2016) Glutamate and mitochondria: two prominent players in the oxidative stress-induced neurodegeneration. Curr Alzheimer Res 13:185–197. https://doi.org/10.2174/1567205013666151218132725
Chakraborty P (2017) Mercury exposure and Alzheimer’s disease in India—an imminent threat? Sci Total Environ 589:232–235. https://doi.org/10.1016/j.scitotenv.2017.02.168
Chan MC, Bautista E, Alvarado-Cruz I, Quintanilla-Vega B, Segovia J (2017) Inorganic mercury prevents the differentiation of SH-SY5Y cells: amyloid precursor protein, microtubule associated proteins and ROS as potential targets. J Trace Elem Med Biol 41:119–128. https://doi.org/10.1016/j.jtemb.2017.02.002
Cheng JP, Shi W, Lin XY (2005) Effects of mercury contaminated rice from typical chemical plant area in China on nitric oxide changes and c-fos expression of rats brain. J Environ Sci 17:177–180
Cheng J, Yang Y, Ma J, Wang W, Liu X, Sakamoto M, Qu Y, Shi W (2009) Assessing noxious effects of dietary exposure to methylmercury, PCBs and Se coexisting in environmentally contaminated rice in male mice. Environ Int 35:619–625. https://doi.org/10.1016/j.envint.2008.12.006
Chin-Chan M, Segovia J, Quintanar L, Arcos-López T, Hersh LB, Chow KM, Rodgers DW, Quintanilla-Vega B (2015) Mercury reduces the enzymatic activity of neprilysin in differentiated SH-SY5Y cells. Toxicol Sci 145:128–137. https://doi.org/10.1093/toxsci/kfv037
Choi B, Yeum KJ, Park SJ, Kim KN, Joo NS (2015) Elevated serum ferritin and mercury concentrations are associated with hypertension; analysis of the fourth and fifth Korea national health and nutrition examination survey (KNHANES IV-2, 3, 2008–2009 and V-1, 2010). Environ Toxicol 30:101–108. https://doi.org/10.1002/tox.21899
Chong JR, Chai YL, Lee JH, Howlett D, Attems J, Ballard CG, Aarsland D, Francis PT, Chen CP, Lai MK (2017) Increased transforming growth factor β2 in the neocortex of Alzheimer’s disease and dementia with Lewy bodies is correlated with disease severity and soluble Aβ 42 load. J Alzheimers Dis 56:157–166. https://doi.org/10.3233/JAD-160781
Cordy P, Veiga MM, Salih I, Al-Saadi S, Console S, Garcia O, Mesa LA, Velásquez-López PC, Roeser M (2011) Mercury contamination from artisanal gold mining in Antioquia, Colombia: the world’s highest per capita mercury pollution. Sci Total Environ 410:154–160. https://doi.org/10.1016/j.scitotenv.2011.09.006
Cornett CR, Markesbery WR, Ehmann WD (1998a) Imbalances of trace elements related to oxidative damage in Alzheimer’s disease brain. Neurotoxicology 19:339–345
Cornett CR, Ehmann WD, Wekstein DR, Markesbery WR (1998b) Trace elements in Alzheimer’s disease pituitary glands. Biol Trace Elem Res 62:107–114
Crichton RR, Dexter D, Ward RJ (2008) Metal based neurodegenerative diseases—from molecular mechanisms to therapeutic strategies. Coord Chem Rev 252:1189–1199. https://doi.org/10.1016/j.ccr.2007.10.019
Crous-Bou M, Minguillón C, Gramunt N, Molinuevo JL (2017) Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimers Res Ther 9:71. https://doi.org/10.1186/s13195-017-0297-z
Curtis JT, Chen Y, Buck DJ, Davis RL (2011) Chronic inorganic mercury exposure induces sex-specific changes in central TNFα expression: importance in autism? Neurosci Lett 504:40–44. https://doi.org/10.1016/j.neulet.2011.08.053
Dadar M, Adel M, Nasrollahzadeh Saravi H, Fakhri Y (2017) Trace element concentration and its risk assessment in common kilka (Clupeonella cultriventris caspia Bordin, 1904) from southern basin of Caspian Sea. Toxin Rev 36:222–227. https://doi.org/10.1080/15569543.2016.1274762
van Dalen JW, Caan MW, van Gool WA, Richard E (2017) Neuropsychiatric symptoms of cholinergic deficiency occur with degradation of the projections from the nucleus basalis of Meynert. Brain Imaging Behav 11:1707–1719 https://doi.org/10.1007/s11682-016-9631-5
Darreh-Shori T (2016) New ligands of choline acetyltransferase as therapeutics and in vivo functional biomarkers in Alzheimer’s disease. Neurobiol Aging:S29. https://doi.org/10.1016/j.neurobiolaging.2016.01.126
Dawkins E, Small DH (2014) Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer’s disease. J Neurochem 129:756–769. https://doi.org/10.1111/jnc.12675
Dias C, Lourenço CF, Ferreiro E, Barbosa RM, Laranjinha J, Ledo A (2016) Age-dependent changes in the glutamate-nitric oxide pathway in the hippocampus of the triple transgenic model of Alzheimer’s disease: implications for neurometabolic regulation. Neurobiol Aging 46:84–95. https://doi.org/10.1016/j.neurobiolaging.2016.06.012
Dimitrov M, Alattia J-R, Lemmin T, Lehal R, Fligier A, Houacine J, Hussain I, Radtke F, Dal Peraro M, Beher D (2013) Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production. Nat Commun 4:2246. https://doi.org/10.1038/ncomms3246
Djordjevic J, Jones-Gotman M, De Sousa K, Chertkow H (2008) Olfaction in patients with mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 29:693–706. https://doi.org/10.1016/j.neurobiolaging.2006.11.014
Dórea JG (2017) Low-dose thimerosal in pediatric vaccines: adverse effects in perspective. Environ Res 152:280–293. https://doi.org/10.1016/j.envres.2016.10.028
Du X, Qiu S, Wang Z, Wang R, Wang C, Tian J, Liu Q (2014) Direct interaction between selenoprotein P and tubulin. Int J Mol Sci 15:10199–10214. https://doi.org/10.3390/ijms150610199
Dursun E, Gezen-Ak D, Hanağası H, Bilgiç B, Lohmann E, Ertan S, Atasoy İL, Alaylıoğlu M, Araz ÖS, Önal B (2015) The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer’s disease, mild cognitive impairment or Parkinson’s disease. J Neuroimmunol 283:50–57. https://doi.org/10.1016/j.jneuroim.2015.04.014
Echeverria D, Woods JS, Heyer NJ, Martin MD, Rohlman DS, Farin FM, Li T (2010) The association between serotonin transporter gene promotor polymorphism (5-HTTLPR) and elemental mercury exposure on mood and behavior in humans. J Toxicol Environ Health A 73:1003–1020. https://doi.org/10.1080/15287390903566591
Ehmann W, Markesbery W, Alauddin M, Hossain T, Brubaker E (1986) Brain trace elements in Alzheimer’s disease. Neurotoxicology 7:195–206
El-Ansary A, Bjørklund G, Tinkov AA, Skalny AV, Al Dera H (2017) Relationship between selenium, lead, and mercury in red blood cells of Saudi autistic children. Metab Brain Dis 32:1073–1080. https://doi.org/10.1007/s11011-017-9996-1
El-Saeed GS, Abdel Maksoud SA, Bassyouni HT, Raafat J, Agybi MH, Wahby AA, Aly HM (2016) Mercury toxicity and DNA damage in patients with Down syndrome. Med Res J 15:22–26. https://doi.org/10.1097/01.MJX.0000483973.37399.e7
Fallin D, Cohen A, Essioux L, Chumakov I, Blumenfeld M, Cohen D, Schork NJ (2001) Genetic analysis of case/control data using estimated haplotype frequencies: application to APOE locus variation and Alzheimer’s disease. Genome Res 11:143–151. https://doi.org/10.1101/gr.148401
Falluel-Morel A, Sokolowski K, Sisti HM, Zhou X, Shors TJ, DiCicco-Bloom E (2007) Developmental mercury exposure elicits acute hippocampal cell death, reductions in neurogenesis, and severe learning deficits during puberty. J Neurochem 103:1968–1981. https://doi.org/10.1111/j.1471-4159.2007.04882.x
Farina M, Aschner M (2017) Methylmercury-induced neurotoxicity: focus on pro-oxidative events and related consequences. Adv Neurobiol 18:267–286. https://doi.org/10.1007/978-3-319-60189-2_13
Farina M, Dahm K, Schwalm F, Brusque A, Frizzo M, Zeni G, Souza D, Rocha J (2003) Methylmercury increases glutamate release from brain synaptosomes and glutamate uptake by cortical slices from suckling rat pups: modulatory effect of ebselen. Toxicol Sci 73:135–140. https://doi.org/10.1093/toxsci/kfg058
Farina M, Rocha JB, Aschner M (2011) Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies. Life Sci 89:555–563. https://doi.org/10.1016/j.lfs.2011.05.019
Faro L, Do Nascimento J, Alfonso M, Duran R (2002) Mechanism of action of methylmercury on in vivo striatal dopamine release: possible involvement of dopamine transporter. Neurochem Int 40:455–465. https://doi.org/10.1016/S0197-0186(01)00098-5
Fonfría E, Vilaró MT, Babot Z, Rodríguez-Farré E, Sunol C (2005) Mercury compounds disrupt neuronal glutamate transport in cultured mouse cerebellar granule cells. J Neurosci Res 79:545–553. https://doi.org/10.1002/jnr.20375
Fontela YC, Kadavath H, Biernat J, Riedel D, Mandelkow E, Zweckstetter M (2017) Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein tau. Nat Commun 8:1981. https://doi.org/10.1038/s41467-017-02230-8
Francis PT (2005) The interplay of neurotransmitters in Alzheimer’s disease. CNS Spectrums 10:6–9. https://doi.org/10.1017/S1092852900014164
Franciscato C, Goulart F, Lovatto N, Duarte F, Flores E, Dressler V, Peixoto N, Pereira M (2009) ZnCl2 exposure protects against behavioral and acetylcholinesterase changes induced by HgCl2. Int J Dev Neurosci 27:459–468. https://doi.org/10.1016/j.ijdevneu.2009.05.002
Frasco M, Fournier D, Carvalho F, Guilhermino L (2005) Do metals inhibit acetylcholinesterase (AChE)? Implementation of assay conditions for the use of AChE activity as a biomarker of metal toxicity. Biomarkers 10:360–375. https://doi.org/10.1080/13547500500264660
Frenkel GD, Cain R, Chao ES-E (1985) Exposure of DNA to methyl mercury results in an increase in the rate of its transcription by RNA polymerase II. Biochem Biophys Res Commun 127:849–856. https://doi.org/10.1016/S0006-291X(85)80021-8
Fujimura M, Usuki F (2012) Differing effects of toxicants (methylmercury, inorganic mercury, lead, amyloid β, and rotenone) on cultured rat cerebrocortical neurons: differential expression of rho proteins associated with neurotoxicity. Toxicol Sci 126:506–514. https://doi.org/10.1093/toxsci/kfr352
Fujimura M, Usuki F, Sawada M, Takashima A (2009) Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of the c-Jun-N-terminal kinase pathway in the cerebral cortex, but not in the hippocampus of the mouse brain. Neurotoxicology 30:1000–1007. https://doi.org/10.1016/j.neuro.2009.08.001
Fung YK, Meade AG, Rack EP, Blotcky AJ, Claassen JP, Beatty MW, Durham T (1995) Determination of blood mercury concentrations in Alzheimer’s patients. J Toxicol Clin Toxicol 33:243–247. https://doi.org/10.3109/15563659509017991
Fung YK, Meade AG, Rack EP, Blotcky AJ (1997) Brain mercury in neurodegenerative disorders. J Toxicol Clin Toxicol 35:49–54. https://doi.org/10.3109/15563659709001165
Gardner RM, Nyland JF, Evans SL, Wang SB, Doyle KM, Crainiceanu CM, Silbergeld EK (2009) Mercury induces an unopposed inflammatory response in human peripheral blood mononuclear cells in vitro. Environ Health Perspect 117:1932. https://doi.org/10.1289/ehp.0900855
Gardner RM, Nyland JF, Silva IA, Ventura AM, de Souza JM, Silbergeld EK (2010) Mercury exposure, serum antinuclear/antinucleolar antibodies, and serum cytokine levels in mining populations in Amazonian Brazil: a cross-sectional study. Environ Res 110:345–354. https://doi.org/10.1016/j.envres.2010.02.001
Gerhardsson L, Aaseth J (2016) Guidance for clinical treatment of metal poisonings—use and misuse of chelating agents. Chelation therapy in the treatment of metal intoxication. Academic Press, London, pp 313–341
Gerhardsson L, Lundh T, Minthon L, Londos E (2008) Metal concentrations in plasma and cerebrospinal fluid in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 25:508–515. https://doi.org/10.1159/000129365
Giacoppo S, Galuppo M, Calabro RS, D’Aleo G, Marra A, Sessa E, Bua DG, Potorti AG, Dugo G, Bramanti P, Mazzon E (2014) Heavy metals and neurodegenerative diseases: an observational study. Biol Trace Elem Res 161:151–160. https://doi.org/10.1007/s12011-014-0094-5
Girek M, Szymański P (2019) Tacrine hybrids as multi-target-directed ligands in Alzheimer’s disease: influence of chemical structures on biological activities. Chem Pap 73:269–289. https://doi.org/10.1007/s11696-018-0590-8
Gnanashanmugam G, Balakrishnan R, Somasundaram SP, Parimalam N, Rajmohan P, Pranesh MB (2018) Mercury toxicity following unauthorized siddha medicine intake—a mimicker of acquired neuromyotonia—report of 32 cases. Ann Indian Acad Neurol 21:49–56. https://doi.org/10.4103/aian.AIAN_274_17
Gonzalez-Dominguez R, Garcia-Barrera T, Gomez-Ariza JL (2014) Homeostasis of metals in the progression of Alzheimer’s disease. Biometals 27:539–549. https://doi.org/10.1007/s10534-014-9728-5
Gowert NS, Donner L, Chatterjee M, Eisele YS, Towhid ST, Münzer P, Walker B, Ogorek I, Borst O, Grandoch M (2014) Blood platelets in the progression of Alzheimer’s disease. PLoS One 9:e90523. https://doi.org/10.1371/journal.pone.0090523
Guida N, Laudati G, Mascolo L, Cuomo O, Anzilotti S, Sirabella R, Santopaolo M, Galgani M, Montuori P, Di Renzo G (2016) MC1568 inhibits thimerosal-induced apoptotic cell death by preventing HDAC4 up-regulation in neuronal cells and in rat prefrontal cortex. Toxicol Sci 154:227–240. https://doi.org/10.1093/toxsci/kfw157
Guzzi G, Grandi M, Cattaneo C, Calza S, Minoia C, Ronchi A, Gatti A, Severi G (2006) Dental amalgam and mercury levels in autopsy tissues: food for thought. Am J Forensic Med Pathol 27:42–45. https://doi.org/10.1097/01.paf.0000201177.62921.c8
Guzzi G, Ronchi A, Barbaro M, Soldarini A, Pigatto PD (2016) Levels of mercury in patient with mercury dental amalgam. Toxicology Letters 258:S113
Hahn L, Kloiber R, Vimy M, Takahashi Y, Lorscheider F (1989) Dental “silver” tooth fillings: a source of mercury exposure revealed by whole-body image scan and tissue analysis. FASEB J 3:2641–2646. https://doi.org/10.1096/fasebj.3.14.2636872
Haley BE (2007) The relationship of the toxic effects of mercury to exacerbation of the medical condition classified as Alzheimer’s disease. Med Veritas 4:1484–1498. https://doi.org/10.1588/medver.2007.04.00164
Hanzel CE, Pichet-Binette A, Pimentel LS, Iulita MF, Allard S, Ducatenzeiler A, Do Carmo S, Cuello AC (2014) Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer’s disease. Neurobiol Aging 35:2249–2262. https://doi.org/10.1016/j.neurobiolaging.2014.03.026
Hardy J (2017) The discovery of Alzheimer-causing mutations in the APP gene and the formulation of the “amyloid cascade hypothesis”. FEBS J 284:1040–1044. https://doi.org/10.1111/febs.14004
Hartley D, Blumenthal T, Carrillo M, DiPaolo G, Esralew L, Gardiner K, Granholm A-C, Iqbal K, Krams M, Lemere C (2015) Down syndrome and Alzheimer's disease: common pathways, common goals. Alzheimers Dement 11:700–709. https://doi.org/10.1016/j.jalz.2014.10.007
Herculano A, Crespo-Lopez M, Lima S, Picanço-Diniz D, Do Nascimento J (2006) Methylmercury intoxication activates nitric oxide synthase in chick retinal cell culture. Braz J Med Biol Res 39:415–418. https://doi.org/10.1590/S0100-879X2006000300013
Higueras P, Fernández-Martínez R, Esbrí JM, Rucandio I, Loredo J, Ordónez A, Alvarez R (2014) Mercury soil pollution in Spain: a review. In: Jiménez E., Cabañas B, Lefebvre G (eds) Environment, Energy and Climate Change I. Springer, Cham, pp 135–158. https://doi.org/10.1007/698_2014_280
Himi T, Ikeda M, Sato I, Yuasa T, S-i M (1996) Purkinje cells express neuronal nitric oxide synthase after methylmercury administration. Brain Res 718:189–192. https://doi.org/10.1016/0006-8993(96)00017-0
Hock C, Drasch G, Golombowski S, Müller-Spahn F, Willershausen-Zönnchen B, Schwarz P, Hock U, Growdon J, Nitsch R (1998) Increased blood mercury levels in patients with Alzheimer’s disease. J Neural Transm 105:59–68. https://doi.org/10.1007/s007020050038
Holmes P, James K, Levy L (2009) Is low-level environmental mercury exposure of concern to human health? Sci Total Environ 408:171–182. https://doi.org/10.1016/j.scitotenv.2009.09.043
Holmquist L, Stuchbury G, Berbaum K, Muscat S, Young S, Hager K, Engel J, Münch G (2007) Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias. Pharmacol Ther 113:154–164. https://doi.org/10.1016/j.pharmthera.2006.07.001
Homme KG, Kern JK, Haley BE, Geier DA, King PG, Sykes LK, Geier MR (2014) New science challenges old notion that mercury dental amalgam is safe. Biometals 27:19–24. https://doi.org/10.1007/s10534-013-9700-9
Hoozemans J, Rozemuller A, Janssen I, De Groot C, Veerhuis R, Eikelenboom P (2001) Cyclooxygenase expression in microglia and neurons in Alzheimer’s disease and control brain. Acta Neuropathol 101:2–8. https://doi.org/10.1007/s004010000251
Hosnedlova B, Kepinska M, Skalickova S, Fernandez C, Ruttkay-Nedecky B, Peng Q, Baron M, Melcova M, Opatrilova R, Zidkova J, Bjørklund G, Sochor J, Kizek R (2018) Nano-selenium and its nanomedicine applications: a critical review. Int J Nanomedicine 13:2107–2128. https://doi.org/10.2147/IJN.S157541
Hrdina P, Peters D, Singhal R (1976) Effects of chronic exposure to cadmium, lead and mercury of brain biogenic amines in the rat. Res Commun Chem Pathol Pharmacol 15:483–493
Iqbal K, Gong C-X, Liu F (2014) Microtubule-associated protein tau as a therapeutic target in Alzheimer’s disease. Expert Opin Ther Targets 18:307–318. https://doi.org/10.1517/14728222.2014.870156
Islam MZ, Van Dao C, Shiraishi M, Miyamoto A (2016) Methylmercury affects cerebrovascular reactivity to angiotensin II and acetylcholine via rho-kinase and nitric oxide pathways in mice. Life Sci 147:30–38. https://doi.org/10.1016/j.lfs.2016.01.033
Ji X, Jin G, Qu L, Cheng J, Wang W (2006) Effect of chronic exposure by mercury contaminated rice on neurotransmitter level changes in rat brain (in Chinese). Huan Jing Ke Xue 27:142–145
Juarez B, Martınez M, Montante M, Dufour L, Garcıa E, Jimenez-Capdeville M (2002) Methylmercury increases glutamate extracellular levels in frontal cortex of awake rats. Neurotoxicol Teratol 24:767–771. https://doi.org/10.1016/S0892-0362(02)00270-2
Kanda H, Shinkai Y, Kumagai Y (2014) S-Mercuration of cellular proteins by methylmercury and its toxicological implications. J Toxicol Sci 39:687–700. https://doi.org/10.2131/jts.39.687
Keeney JT, Butterfield DA (2015) Vitamin D deficiency and Alzheimer disease: common links. Neurobiol Dis 84:84–98. https://doi.org/10.1016/j.nbd.2015.06.020
Kern JK, Geier DA, Audhya T, King PG, Sykes LK, Geier MR (2012) Evidence of parallels between mercury intoxication and the brain pathology in autism. Acta Neurobiol Exp (Wars) 72:113–153
Kern JK, Geier DA, Bjørklund G, King PG, Homme KG, Haley BE, Sykes LK, Geier MR (2014) Evidence supporting a link between dental amalgams and chronic illness, fatigue, depression, anxiety, and suicide. Neuroendocrinol Lett 35:535–552
Kim DK, Park JD, Choi BS (2014) Mercury-induced amyloid-beta (Aβ) accumulation in the brain is mediated by disruption of Aβ transport. J Toxicol Sci 39:625–635. https://doi.org/10.2131/jts.39.625
Kim SA, Kwon Y, Kim S, Joung H (2016) Assessment of dietary mercury intake and blood mercury levels in the Korean population: results from the Korean national environmental health survey 2012–2014. Int J Environ Res Public Health 13:877. https://doi.org/10.3390/ijerph13090877
Kim A, Lim S, Kim Y (2018) Metal ion effects on Aβ and tau aggregation. Int J Mol Sci 19:128. https://doi.org/10.3390/ijms19010128
Korbas M, O'Donoghue JL, Watson GE, Pickering IJ, Singh SP, Myers GJ, Clarkson TW, George GN (2010) The chemical nature of mercury in human brain following poisoning or environmental exposure. ACS Chem Neurosci 1:810–818. https://doi.org/10.1021/cn1000765
Koseoglu E, Koseoglu R, Kendirci M, Saraymen R, Saraymen B (2017) Trace metal concentrations in hair and nails from Alzheimer’s disease patients: relations with clinical severity. J Trace Elem Med Biol 39:124–128. https://doi.org/10.1016/j.jtemb.2016.09.002
Kostka B, Krajewska U, Rieske P (1997) Platelet activation by mercuric compounds. Platelets 8:413–417. https://doi.org/10.1080/09537109777104
Kröger E, Verreault R, Carmichael PH, Lindsay J, Julien P, Dewailly E, Ayotte P, Laurin D (2009) Omega-3 fatty acids and risk of dementia: the Canadian study of health and aging. Am J Clin Nutr 90(1):184–192. https://doi.org/10.3945/ajcn.2008.26987
Kruyer A, Soplop N, Strickland S, Norris EH (2015) Chronic hypertension leads to neurodegeneration in the TgSwDI mouse model of Alzheimer’s disease. Hypertension 66:175–182. https://doi.org/10.1161/HYPERTENSIONAHA.115.05524
Kryscio RJ, Abner EL, Caban-Holt A, Lovell M, Goodman P, Darke AK, Yee M, Crowley J, Schmitt FA (2017) Association of antioxidant supplement use and dementia in the prevention of Alzheimer’s disease by vitamin E and selenium trial (PREADViSE). JAMA Neurol 74:567–573. https://doi.org/10.1001/jamaneurol.2016.5778
Kumar SV, Bhattacharya S (2000) In vitro toxicity of mercury, cadmium, and arsenic to platelet aggregation: influence of adenylate cyclase and phosphodiesterase activity. In Vitr Mol Toxicol 13:137–144
Kumar G, Srivastava A, Sharma SK, Gupta YK (2014) Safety evaluation of mercury based Ayurvedic formulation (Sidh Makardhwaj) on brain cerebrum, liver & kidney in rats. Indian J Med Res 139:610
Le Guennec K, Veugelen S, Quenez O, Szaruga M, Rousseau S, Nicolas G, Wallon D, Fluchere F, Frébourg T, De Strooper B (2017) Deletion of exons 9 and 10 of the presenilin 1 gene in a patient with early-onset Alzheimer disease generates longer amyloid seeds. Neurobiol Dis 104:97–103. https://doi.org/10.1016/j.nbd.2017.04.020
Lee JY, Kim JH, Choi DW, Lee DW, Park JH, Yoon HJ, Pyo HS, Kwon HJ, Park KS (2012) The association of heavy metal of blood and serum in the Alzheimer’s diseases. Toxicol Res 28:93–98. https://doi.org/10.5487/TR.2012.28.2.093
Leong CC, Syed NI, Lorscheider FL (2001) Retrograde degeneration of neurite membrane structural integrity of nerve growth cones following in vitro exposure to mercury. Neuroreport 12:733–737. https://doi.org/10.1097/00001756-200103260-00024
Li X, Long J, He T, Belshaw R, Scott J (2015) Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer’s disease. Sci Rep 5:12393. https://doi.org/10.1038/srep12393
Liang J, Feng C, Zeng G, Zhong M, Gao X, Li X, He X, Li X, Fang Y, Mo D (2017) Atmospheric deposition of mercury and cadmium impacts on topsoil in a typical coal mine city, Lianyuan, China. Chemosphere 189:198–205. https://doi.org/10.1016/j.chemosphere.2017.09.046
Lim K-M, Kim S, Noh J-Y, Kim K, Jang W-H, Bae O-N, Chung S-M, Chung J-H (2010) Low-level mercury can enhance procoagulant activity of erythrocytes: a new contributing factor for mercury-related thrombotic disease. Environ Health Perspect 118:928. https://doi.org/10.1289/ehp.0901473
Liu W, Wang X, Zhang R, Zhou Y (2009) Effects of postnatal exposure to methylmercury on spatial learning and memory and brain NMDA receptor mRNA expression in rats. Toxicol Lett 188:230–235. https://doi.org/10.1016/j.toxlet.2009.04.021
Liu Y, Zhang W, Zhao J, Lin X, Liu J, Cui L, Gao Y, Zhang TL, Li B, Li YF (2018) Selenoprotein P as the major transporter for mercury in serum from methylmercury-poisoned rats. J Trace Elem Med Biol 50:589–595. https://doi.org/10.1016/j.jtemb.2018.04.013
Lombardo S, Maskos U (2015) Role of the nicotinic acetylcholine receptor in Alzheimer’s disease pathology and treatment. Neuropharmacology 96:255–262. https://doi.org/10.1016/j.neuropharm.2014.11.018
MacKenzie IR (1996) Serum trace metals in patients with “Alzheimer-type” senile plaques. Trace Elem Electrolytes 13:107–108
Maximino C, Araujo J, Leão LKR, Grisolia ABA, Oliveira KRM, Lima MG, Batista EJO, Crespo-López ME, Gouveia A Jr, Herculano AM (2011) Possible role of serotoninergic system in the neurobehavioral impairment induced by acute methylmercury exposure in zebrafish (Danio rerio). Neurotoxicol Teratol 33:727–734. https://doi.org/10.1016/j.ntt.2011.08.006
McHuron EA, Peterson SH, Ackerman JT, Melin SR, Harris JD, Costa DP (2016) Effects of age, colony, and sex on mercury concentrations in California sea lions. Arch Environ Contam Toxicol 70:46–55. https://doi.org/10.1007/s00244-015-0201-4
Mielke MM, Vemuri P, Rocca WA (2014) Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol 6:37. https://doi.org/10.2147/CLEP.S37929
Miller TJ, Grow WA (2004) Mercury decreases the frequency of induced but not spontaneous clustering of acetylcholine receptors. Cell Tissue Res 316:211–219. https://doi.org/10.1007/s00441-004-0878-6
Mirzoian A, Luetje CW (2002) Modulation of neuronal nicotinic acetylcholine receptors by mercury. J Pharmacol Exp Ther 302:560–567. https://doi.org/10.1124/jpet.102.035154
Miyamoto K, Nakanishi H, Moriguchi S, Fukuyama N, Eto K, Wakamiya J, Murao K, Arimura K, Osame M (2001) Involvement of enhanced sensitivity of N-methyl-d-aspartate receptors in vulnerability of developing cortical neurons to methylmercury neurotoxicity. Brain Research 901(1-2):252–258
Monnet-Tschudi F, Zurich M-G, Boschat C, Corbaz A, Honegger P (2006) Involvement of environmental mercury and lead in the etiology of neurodegenerative diseases. Rev Environ Health 21:105–118. https://doi.org/10.1515/REVEH.2006.21.2.105
Moreira MJS, Schwertner C, Jardim JJ, Hashizume LN (2016) Dental caries in individuals with D own syndrome: a systematic review. Int J Paediatr Dent 26:3–12. https://doi.org/10.1111/ipd.12212
Moretto MB, Lermen CL, Morsch VM, Bohrer D, Ineu RP, da Silva AC, Balz D, Schetinger MRC (2004) Effect of subchronic treatment with mercury chloride on NTPDase, 5′-nucleotidase and acetylcholinesterase from cerebral cortex of rats. J Trace Elem Med Biol 17:255–260. https://doi.org/10.1016/S0946-672X(04)80027-0
Moretto M, Funchal C, Santos A, Gottfried C, Boff B, Zeni G, Pessoa-Pureur R, Souza D, Wofchuk S, Rocha J (2005) Ebselen protects glutamate uptake inhibition caused by methyl mercury but does not by Hg2+. Toxicology 214:57–66. https://doi.org/10.1016/j.tox.2005.05.022
Morris MC, Brockman J, Schneider JA, Wang Y, Bennett DA, Tangney CC, van de Rest O (2016) Association of seafood consumption, brain mercury level, and APOE ε4 status with brain neuropathology in older adults. JAMA 315:489–497. https://doi.org/10.1001/jama.2015.19451
Mortazavi S, Neghab M, Anoosheh S, Bahaeddini N, Mortazavi G, Neghab P, Rajaeifard A (2014) High-field MRI and mercury release from dental amalgam fillings. Int J Occup Environ Med 5:316-101-315
Mutkus L, Aschner JL, Syversen T, Aschner M (2005) Methylmercury alters the in vitro uptake of glutamate in GLAST-and GLT-1-transfected mutant CHO-K1 cells. Biol Trace Elem Res 107:231–245. https://doi.org/10.1385/BTER:107:3:231
Mutter J, Curth A, Naumann J, Deth R, Walach H (2010) Does inorganic mercury play a role in Alzheimer’s disease? A systematic review and an integrated molecular mechanism. J Alzheimers Dis 22:357–374. https://doi.org/10.3233/JAD-2010-100705
Nakazawa K, Nagafuchi O, Kawakami T, Inoue T, Yokota K, Serikawa Y, Cyio B, Elvince R (2016) Human health risk assessment of mercury vapor around artisanal small-scale gold mining area, Palu city, Central Sulawesi, Indonesia. Ecotoxicol Environ Saf 124:155–162. https://doi.org/10.1016/j.ecoenv.2015.09.042
Natalello A, Relini A, Penco A, Halabelian L, Bolognesi M, Doglia SM, Ricagno S (2015) Wild type beta-2 microglobulin and DE loop mutants display a common fibrillar architecture. PLoS One 10:e0122449. https://doi.org/10.1371/journal.pone.0122449
Nazıroğlu M, Muhamad S, Pecze L (2017) Nanoparticles as potential clinical therapeutic agents in Alzheimer’s disease: focus on selenium nanoparticles. Expert Rev Clin Pharmacol 10:773–782. https://doi.org/10.1080/17512433.2017.1324781
Ndountse LT, Chan HM (2008) Methylmercury increases N-methyl-D-aspartate receptors on human SH-SY 5Y neuroblastoma cells leading to neurotoxicity. Toxicology 249:251–255. https://doi.org/10.1016/j.tox.2008.05.011
Ng S, Lin C-C, Hwang Y-H, Hsieh W-S, Liao H-F, Chen P-C (2013) Mercury, APOE, and children’s neurodevelopment. Neurotoxicology 37:85–92. https://doi.org/10.1016/j.neuro.2013.03.012
NIH - National Institutes of Health (2018) APP gene: amyloid beta precursor protein. Genetics Home Reference. https://ghr.nlm.nih.gov/gene/APP. Accessed 16 December 2018
Nylander M, Friberg L, Lind B (1987) Mercury concentrations in the human brain and kidneys in relation to exposure from dental amalgam fillings. Swed Dent J 11:179–187
Olcott MC, Bradley ML, Haley BE (1994) Photoaffinity labeling of creatine kinase with 2-azido-and 8-azidoadenosine triphosphate: identification of two peptides from the ATP-binding domain. Biochemistry 33:11935–11941. https://doi.org/10.1021/bi00205a032
Olivieri G, Brack C, Müller-Spahn F, Stähelin H, Herrmann M, Renard P, Brockhaus M, Hock C (2000) Mercury induces cell cytotoxicity and oxidative stress and increases β-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells. J Neurochem 74:231–236. https://doi.org/10.1046/j.1471-4159.2000.0740231.x
Olivieri G, Novakovic M, Savaskan E, Meier F, Baysang G, Brockhaus M, Müller-Spahn F (2002) The effects of β-estradiol on SHSY5Y neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and β-amyloid secretion. Neuroscience 113:849–855. https://doi.org/10.1016/S0306-4522(02)00211-7
Osuntokun BO, Sahota A, Ogunniyi A, Gureje O, Baiyewu O, Adeyinka A, Oluwole S, Komolafe O, Hall K, Unverzagt F (1995) Lack of an association between apolipoprotein E ϵ4 and Alzheimer’s disease in elderly. Nigerians Ann Neurol 38:463–465. https://doi.org/10.1002/ana.410380319
Oudar P, Caillard L, Fillion G (1989) In vitro effect of organic and inorganic mercury on the serotonergic system. Pharmacol Toxicol 65:245–248. https://doi.org/10.1111/j.1600-0773.1989.tb01166.x
Paglia G, Miedico O, Cristofano A, Vitale M, Angiolillo A, Chiaravalle AE, Corso G, Di Costanzo A (2016) Distinctive pattern of serum elements during the progression of Alzheimer’s disease. Sci Rep 6:22769. https://doi.org/10.1038/srep22769
Pamphlett R, Kum Jew S (2015) Different populations of human locus ceruleus neurons contain heavy metals or hyperphosphorylated tau: implications for amyloid-β and tau pathology in Alzheimer’s disease. J Alzheimers Dis 45:437–447. https://doi.org/10.3233/JAD-142445
Papadopoulos P, Tong X-K, Imboden H, Hamel E (2017) Losartan improves cerebrovascular function in a mouse model of Alzheimer’s disease with combined overproduction of amyloid-β and transforming growth factor-β1. J Cereb Blood Flow Metab 37:1959–1970. https://doi.org/10.1177/0271678X16658489
Park HJ, Youn HS (2013) Mercury induces the expression of cyclooxygenase-2 and inducible nitric oxide synthase. Toxicol Ind Health 29:169–174. https://doi.org/10.1177/0748233711427048
Park JH, Lee DW, Park KS, Joung H (2014) Serum trace metal levels in Alzheimer’s disease and normal control groups. Am J Alzheimers Dis Other Demen 29:76–83. https://doi.org/10.1177/1533317513506778
Parsons CG, Stoffler A, Danysz W (2007) Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system—too little activation is bad, too much is even worse. Neuropharmacology 53:699–723. https://doi.org/10.1016/j.neuropharm.2007.07.013
Pendergrass J, Haley B (1997) Inhibition of brain tubulin-guanosine 5′-triphosphate interactions by mercury: similarity to observations in Alzheimer’s diseased brain. Met Ions Biol Syst 34:461–478
Petroni D, Tsai J, Agrawal K, Mondal D, George W (2012) Low-dose methylmercury-induced oxidative stress, cytotoxicity, and tau-hyperphosphorylation in human neuroblastoma (SH-SY5Y) cells. Environ Toxicol 27:549–555. https://doi.org/10.1002/tox.20672
Petroni D, Tsai J, Mondal D, George W (2013) Attenuation of low dose methylmercury and glutamate induced-cytotoxicity and tau phosphorylation by an N-methyl-D-aspartate antagonist in human neuroblastoma (SHSY5Y) cells. Environ Toxicol 28:700–706. https://doi.org/10.1002/tox.20765
Pigatto PD, Costa A, Guzzi G (2018) Are mercury and Alzheimer’s disease linked? Sci Total Environ 613:1579–1580. https://doi.org/10.1016/j.scitotenv.2017.09.036
Pivovarova NB, Andrews SB (2010) Calcium-dependent mitochondrial function and dysfunction in neurons. FEBS J 277:3622–3636. https://doi.org/10.1111/j.1742-4658.2010.07754.x
Rasinger JD, Lundebye AK, Penglase SJ, Ellingsen S, Amlund H (2017) Methylmercury induced neurotoxicity and the influence of selenium in the brains of adult zebrafish (Danio rerio). Int J Mol Sci Mar 18:725. https://doi.org/10.3390/ijms18040725
Raven F, Ward JF, Zoltowska KM, Wan Y, Bylykbashi E, Miller SJ, Shen X, Choi SH, Rynearson KD, Berezovska O (2017) Soluble gamma-secretase modulators attenuate Alzheimer’s β-amyloid pathology and induce conformational changes in presenilin 1. EBioMedicine 24:93–101. https://doi.org/10.1016/j.ebiom.2017.08.028
Reitz C, Brayne C, Mayeux R (2011) Epidemiology of Alzheimer disease. Nat Rev Neurol 7:137. https://doi.org/10.1038/nrneurol.2011.2
Ren MY, Yang LY, Wang LF, Han XM, Dai JR, Pang XG (2018) Spatial trends and pollution assessment for mercury in the surface soils of the Nansi Lake catchment, China. Environ Sci Pollut Res Int 25:2417–2424. https://doi.org/10.1007/s11356-017-0554-5
Richetti SK, Rosemberg DB, Ventura-Lima J, Monserrat JM, Bogo MR, Bonan CD (2011) Acetylcholinesterase activity and antioxidant capacity of zebrafish brain is altered by heavy metal exposure. Neurotoxicology 32:116–122. https://doi.org/10.1016/j.neuro.2010.11.001
Rooney JP (2007) The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology of mercury. Toxicology 234:145–156. https://doi.org/10.1016/j.tox.2007.02.016
Rooney JP (2014) The retention time of inorganic mercury in the brain—a systematic review of the evidence. Toxicol Appl Pharmacol 274:425–435. https://doi.org/10.1016/j.taap.2013.12.011
Roses AD (1998) Apolipoprotein E and Alzheimer’s disease: the tip of the susceptibility iceberg. Ann N Y Acad Sci 855:738–743. https://doi.org/10.1111/j.1749-6632.1998.tb10653.x
Rubinsztein D, Hon J, Stevens F, Pyrah I, Tysoe C, Huppert F, Easton D, Holland A (1999) Apo E genotypes and risk of dementia in Down syndrome. Am J Med Genet 88:344–347. https://doi.org/10.1002/(SICI)1096-8628(19990820)88:4<344::AID-AJMG10>3.0.CO;2-1
Rusina R, Matěj R, Kašparová L, Kukal J, Urban P (2011) Higher aluminum concentration in Alzheimer’s disease after Box-Cox data transformation. Neurotox Res 20(4):329–333. https://doi.org/10.1007/s12640-011-9246-y
Russell SL (2017) Four or more amalgam fillings correlate with higher blood mercury levels in pregnant women but not high enough to be of health concern. J Evid Based Dent Pract 17:139–141. https://doi.org/10.1016/j.jebdp.2017.03.001
Sacuiu S, Insel PS, Mueller S, Tosun D, Mattsson N, Jack CR Jr, DeCarli C, Petersen R, Aisen PS, Weiner MW (2016) Chronic depressive symptomatology in mild cognitive impairment is associated with frontal atrophy rate which hastens conversion to Alzheimer dementia. Am J Geriatr Psychiatry 24:126–135. https://doi.org/10.1016/j.jagp.2015.03.006
Sadleir KR, Kandalepas PC, Buggia-Prévot V, Nicholson DA, Thinakaran G, Vassar R (2016) Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer’s disease. Acta Neuropathol 132:235–256. https://doi.org/10.1007/s00401-016-1558-9
Salinaro AT, Pennisi M, Di Paola R, Scuto M, Crupi R, Cambria MT, Ontario ML, Tomasello M, Uva M, Maiolino L (2018) Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer’s disease and Alzheimer-linked pathologies: modulation by nutritional mushrooms. Immun Ageing 15:8. https://doi.org/10.1186/s12979-017-0108-1
Samir AM, Aref WM (2011) Impact of occupational exposure to elemental mercury on some antioxidative enzymes among dental staff. Toxicol Ind Health 27:779–786. https://doi.org/10.1177/0748233710397420
Samudralwar DL, Diprete CC, Ni BF, Ehmann WD, Markesbery WR (1995) Elemental imbalances in the olfactory pathway in Alzheimer’s disease. J Neurol Sci 130:139–145. https://doi.org/10.1016/0022-510X(95)00018-W
Saxe SR, Wekstein MW, Kryscio RJ, Henry RG, Cornett CR, Snowdon DA, Grant FT, Schmitt FA, Donegan SJ, Wekstein DR, Ehmann WD, Markesbery WR (1999) Alzheimer’s disease, dental amalgam and mercury. J Am Dent Assoc 130:191–199. https://doi.org/10.14219/jada.archive.1999.0168
Schousboe A (2017) A tribute to Mary C. McKenna: glutamate as energy substrate and neurotransmitter—functional interaction between neurons and astrocytes. Neurochem Res 42:4–9. https://doi.org/10.1007/s11064-015-1813-9
Shahar A, Patel KV, Semba RD, Bandinelli S, Shahar DR, Ferrucci L, Guralnik JM (2010) Plasma selenium is positively related to performance in neurological tasks assessing coordination and motor speed. Mov Disord 25:1909–1915. https://doi.org/10.1002/mds.23218
Sharman MJ, Gyengesi E, Liang H, Chatterjee P, Karl T, Li QX, Wenk MR, Halliwell B, Martins RN, Münch G (2019) Assessment of diets containing curcumin, epigallocatechin-3-gallate, docosahexaenoic acid and α-lipoic acid on amyloid load and inflammation in a male transgenic mouse model of Alzheimer’s disease: are combinations more effective? Neurobiol Dis 124:505–519. https://doi.org/10.1016/j.nbd.2018.11.026
Skalny AV, Skalnaya MG, Nikonorov AA, Tinkov AA (2016) Selenium antagonism with mercury and arsenic: from chemistry to population health and demography. In: selenium. Springer, Cham, pp 401–412
Solovyev N, Drobyshev E, Bjørklund G, Dubrovskii Y, Lysiuk R, Rayman MP (2018) Selenium, selenoprotein P, and Alzheimer’s disease: is there a link? Free Radic Biol Med 127:124–133. https://doi.org/10.1016/j.freeradbiomed.2018.02.030
Somavarapu AK, Kepp KP (2016) Loss of stability and hydrophobicity of presenilin 1 mutations causing Alzheimer’s disease. J Neurochem 137:101–111. https://doi.org/10.1111/jnc.13535
Song JW, Choi BS (2013) Mercury induced the accumulation of amyloid beta (Aβ) in PC12 cells: the role of production and degradation of Aβ. Toxicol Res 29:235
Sonkar VK, Kulkarni PP, Dash D (2014) Amyloid β peptide stimulates platelet activation through RhoA-dependent modulation of actomyosin organization. FASEB J 28:1819–1829. https://doi.org/10.1096/fj.13-243691
Spiller HA (2018) Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity. Clin Toxicol 56:313–326. https://doi.org/10.1080/15563650.2017.1400555
Streets DG, Lu Z, Levin L, ter Schure AF, Sunderland EM (2018) Historical releases of mercury to air, land, and water from coal combustion. Sci Total Environ 615:131–140. https://doi.org/10.1016/j.scitotenv.2017.09.207
Sun YH, Nfor ON, Huang JY, Liaw YP (2015) Association between dental amalgam fillings and Alzheimer’s disease: a population-based cross-sectional study in Taiwan Alzheimers. Res Ther 7:65. https://doi.org/10.1186/s13195-015-0150-1
Syversen T, Kaur P (2012) The toxicology of mercury and its compounds. J Trace Elem Med Biol 26:215–226. https://doi.org/10.1016/j.jtemb.2012.02.004
Szabo ST, Harry GJ, Hayden KM, Szabo DT, Birnbaum L (2015) Comparison of metal levels between postmortem brain and ventricular fluid in Alzheimer’s disease and nondemented elderly controls. Toxicol Sci 150:292–300. https://doi.org/10.1093/toxsci/kfv325
Tabaton M, Tamagno E (2007) The molecular link between β-and γ-secretase activity on the amyloid β precursor protein. Cell Mol Life Sci 64:2211–2218. https://doi.org/10.1007/s00018-007-7219-3
Tajeddinn W, Fereshtehnejad SM, Seed Ahmed M, Yoshitake T, Kehr J, Shahnaz T, Milovanovic M, Behbahani H, Höglund K, Winblad B, Cedazo-Minguez A, Jelic V, Järemo P, Aarsland D (2016) Association of platelet serotonin levels in Alzheimer’s disease with clinical and cerebrospinal fluid markers. J Alzheimers Dis 53:621–630. https://doi.org/10.3233/JAD-160022
Talesa VN (2001) Acetylcholinesterase in Alzheimer’s disease. Mech Ageing Dev 122:1961–1969. https://doi.org/10.1016/S0047-6374(01)00309-8
Thompson C, Markesbery W, Ehmann W, Mao Y, Vance D (1988) Regional brain trace-element studies in Alzheimer’s disease. Neurotoxicology 9:1–7
Toimela T, Tähti H (2004) Mitochondrial viability and apoptosis induced by aluminum, mercuric mercury and methylmercury in cell lines of neural origin. Arch Toxicol 78:565–574. https://doi.org/10.1007/s00204-004-0575-y
Tolonen M, Halme M, Sarna S (1985) Vitamin E and selenium supplementation in geriatric patients. Biol Trace Elem Res 7:161. https://doi.org/10.1007/BF02916538
Tratnik JS, Falnoga I, Trdin A, Mazej D, Fajon V, Miklavčič A, Kobal AB, Osredkar J, Briški AS, Krsnik M (2017) Prenatal mercury exposure, neurodevelopment and apolipoprotein E genetic polymorphism. Environ Res 152:375–385. https://doi.org/10.1016/j.envres.2016.08.035
Tsai C-L, Jang T-H, Wang L-H (1995) Effects of mercury on serotonin concentration in the brain of tilapia, Oreochromis mossambicus. Neurosci Lett 184:208–211. https://doi.org/10.1016/0304-3940(94)11208-Z
Uki M, Narahashi T (1996) Modulation of serotonin-induced currents by metals in mouse neuroblastoma cells. Arch Toxicol 70:652–660. https://doi.org/10.1007/s002040050325
Vance DE, Ehmann WD, Markesbery WR (1988) Trace element imbalances in hair and nails of Alzheimer's disease patients. Neurotoxicology 9:197–208.
Varma VR, Varma S, An Y, Hohman TJ, Seddighi S, Casanova R, Beri A, Dammer EB, Seyfried NT, Pletnikova O (2017) Alpha-2 macroglobulin in Alzheimer’s disease: a marker of neuronal injury through the RCAN1 pathway. Mol Psychiatry 22:13. https://doi.org/10.1038/mp.2016.206
Vassar R, Kovacs DM, Yan R, Wong PC (2009) The β-secretase enzyme BACE in health and Alzheimer’s disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 29:12787–12794. https://doi.org/10.1523/JNEUROSCI.3657-09.2009
Vejrup K, Brantsæter AL, Knutsen HK, Magnus P, Alexander J, Kvalem HE, Meltzer HM, Haugen M (2014) Prenatal mercury exposure and infant birth weight in the Norwegian mother and child cohort study. Public Health Nutr 17:2071–2080. https://doi.org/10.1017/S1368980013002619
Walach H, Mutter J, Deth R (2015) Inorganic mercury and Alzheimer’s disease—results of a review and a molecular mechanism. In: Martin CR, Preedy VR (eds) Diet and Nutrition in Dementia and Cognitive Decline. Elsevier, Amsterdam, pp 593–601. https://doi.org/10.1016/B978-0-12-407824-6.00055-0
Wallace TL, Bertrand D (2013) Importance of the nicotinic acetylcholine receptor system in the prefrontal cortex. Biochem Pharmacol 85:1713–1720. https://doi.org/10.1016/j.bcp.2013.04.001
Wang Q, Yang X, Zhang B, Yang X, Wang K (2013) Cinnabar is different from mercuric chloride in mercury absorption and influence on the brain serotonin level. Basic Clin Pharmacol Toxicol 112:412–417. https://doi.org/10.1111/bcpt.12045
Ward NI, Mason JA (1987) Neutron activation analysis techniques for identifying elemental status in Alzheimer's disease. J Radioanal Nucl Chem 113: 515–526. https://doi.org/10.1007/BF02050527
Warfvinge K, Hansson H, Hultman P (1995) Systemic autoimmunity due to mercury vapor exposure in genetically susceptible mice: dose-response studies. Toxicol Appl Pharmacol 132:299–309. https://doi.org/10.1006/taap.1995.1111
Wenstrup D, Ehmann WD, Markesbery WR (1990) Trace element imbalances in isolated subcellular fractions of Alzheimer’s disease. Brain Res 533:125–131
Williams DR, Gonzalez HM, Neighbors H, Nesse R, Abelson JM, Sweetman J, Jackson JS (2007) Prevalence and distribution of major depressive disorder in African Americans, Caribbean blacks, and non-Hispanic whites: results from the National Survey of American life. Arch Gen Psychiatry 64:305–315
Wiseman FK, Al-Janabi T, Hardy J, Karmiloff-Smith A, Nizetic D, Tybulewicz VL, Fisher EM, Strydom A (2015) A genetic cause of Alzheimer disease: mechanistic insights from down syndrome. Nat Rev Neurosci 16:564. https://doi.org/10.1038/nrn3983
Xia D, Watanabe H, Wu B, Lee SH, Li Y, Tsvetkov E, Bolshakov VY, Shen J, Kelleher RJ (2015) Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer’s disease. Neuron 85:967–981. https://doi.org/10.1016/j.neuron.2015.02.010
Xu F, Farkas S, Kortbeek S, Zhang F-X, Chen L, Zamponi GW, Syed NI (2012) Mercury-induced toxicity of rat cortical neurons is mediated through N-methyl-D-aspartate receptors. Mol Brain 5:30. https://doi.org/10.1186/1756-6606-5-30
Yamamoto M, Khan N, Muniroh M, Motomura E, Yanagisawa R, Matsuyama T, Vogel CF (2017) Activation of interleukin-6 and-8 expressions by methylmercury in human U937 macrophages involves RelA and p50. J Appl Toxicol 37:611–620. https://doi.org/10.1002/jat.3411
Yan R, Vassar R (2014) Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol 13:319–329. https://doi.org/10.1016/S1474-4422(13)70276-X
Yang DJ, Shi S, Zheng LF, Yao TM, Ji LN (2010) Mercury (II) promotes the in vitro aggregation of tau fragment corresponding to the second repeat of microtubule-binding domain: coordination and conformational transition. Biopolymers 93:1100–1107. https://doi.org/10.1002/bip.21527
Yang DJ, Shi S, Yao TM, Ji LN (2011) The impacts of Hg (II) tightly binding on the Alzheimer’s tau construct R3: misfolding and aggregation. Bull Chem Soc Jpn 84:1362–1367. https://doi.org/10.1246/bcsj.20110133
Yang H, Turner S, Rose NL (2016) Mercury pollution in the lake sediments and catchment soils of anthropogenically-disturbed sites across England. Environ Pollut 219:1092–1101. https://doi.org/10.1016/j.envpol.2016.09.012
Yang YW, Liou SH, Hsueh YM, Lyu WS, Liu CS, Liu HJ, Chung MC, Hung PH, Chung CJ (2018) Risk of Alzheimer’s disease with metal concentrations in whole blood and urine: a case-control study using propensity score matching. Toxicol Appl Pharmacol 356:8–14. https://doi.org/10.1016/j.taap.2018.07.015
Yao K, Li Y, Zhu X, Zhu L (2014) Individual and joint effects of lead and mercury on acetylcholinesterase activity in goldfish brain. Fresenius Environ Bull 23:2514–2519
Yin L, Yu K, Lin S, Song X, Yu X (2016) Associations of blood mercury, inorganic mercury, methyl mercury and bisphenol a with dental surface restorations in the US population, NHANES 2003–2004 and 2010–2012. Ecotoxicol Environ Saf 134:213–225. https://doi.org/10.1016/j.ecoenv.2016.09.001
Ynalvez R, Gutierrez J, Gonzalez-Cantu H (2016) Mini-review: toxicity of mercury as a consequence of enzyme alteration. Biometals 29:781–788. https://doi.org/10.1007/s10534-016-9967-8
Yousuf FA, Iqbal MP (2015) Apolipoprotein E (Apo E) gene polymorphism and coronary heart disease in Asian populations. Pak J Pharm Sci 28
Zhang S, Rocourt C, Cheng WH (2010) Selenoproteins and the aging brain. Mech Ageing Dev 131:253–260. https://doi.org/10.1016/j.mad.2010.02.006
Zhou Y, Aamir M, Liu K, Yang F, Liu W (2018) Status of mercury accumulation in agricultural soil across China: spatial distribution, temporal trend, influencing factor and risk assessment. Environ Pollut Sep 240:116–124. https://doi.org/10.1016/j.envpol.2018.03.086
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Bjørklund, G., Tinkov, A.A., Dadar, M. et al. Insights into the Potential Role of Mercury in Alzheimer’s Disease. J Mol Neurosci 67, 511–533 (2019). https://doi.org/10.1007/s12031-019-01274-3
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DOI: https://doi.org/10.1007/s12031-019-01274-3