Metals Toxicity Associated with Oxidative Stress and Altered Level of Antioxidants in the Pathogenesis of Alzheimer’s Disease

Downloads

Published

2023-09-08

DOI:

https://doi.org/10.55229/ijbs.v26i2.10

Keywords:

Alzheimer’s Disease, Amyloid-beta, Metals toxicity, Oxidative stress, Antioxidants

Dimensions Badge

Issue

Vol. 26 No. 02 (2023): Indian Journal of Behavioural Sciences

Section

REVIEW ARTICLE

License

Copyright (c) 2023 Jyoti Yadav, Anoop K. Verma, Anu Singla, R. K. Garg

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

You are free to:

  • The licensor cannot revoke these freedoms as long as you follow the license terms.

Under the following terms:

  • No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Crossref
Scopus
Google Scholar
Europe PMC

Authors

  • Jyoti Yadav Department of Forensic Medicine & Toxicology, King George’s Medical University, Lucknow, Uttar Pradesh, India.
  • Anoop K. Verma Department of Forensic Medicine & Toxicology, King George’s Medical University, Lucknow, Uttar Pradesh, India.
  • Anu Singla Dr. A.P.J. Abdul Kalam Institute of Forensic science & Criminology, Bundelkhand University, Jhansi, Uttar Pradesh, India.
  • R. K. Garg Department of Neurology, King George’s Medical University, Lucknow, Uttar Pradesh, India.

Abstract

In this review, metals role in the production of oxidative stress and its association with the altered antioxidant levels have been focused in AD. We have found that metals accumulation is responsible for increased oxidative stress that induces a critical event in the pathogenesis of AD. These pathological changes might alter the antioxidant levels to attenuate free radicals in the body. Some nutritional supplement such as Vitamin E, vitamin C, and vitamin B12 may also have essential roles in the treatment of AD. Alzheimer’s disease is one of the most common forms of dementia in the elderly population. Altered levels of trace metals and heavy metals accumulation such as Iron, Copper, Zinc, Lead, Cadmium, and Mercury have been associated with oxidative stress production in Alzheimer’s disease (AD) pathogenesis. Metals accumulation is also associated with overproduced amyloid-beta may alter the level of antioxidants in AD patients.  Dietary intake of essential antioxidants has been suggested to delay or prevent cognitive impairment by many studies.   

How to Cite

Yadav, J., Verma, A. K., Singla, A., & R. K. Garg. (2023). Metals Toxicity Associated with Oxidative Stress and Altered Level of Antioxidants in the Pathogenesis of Alzheimer’s Disease. Indian Journal of Behavioural Sciences, 26(02), 138–152. https://doi.org/10.55229/ijbs.v26i2.10

Downloads

Download data is not yet available.

Author Biographies

Jyoti Yadav, Department of Forensic Medicine & Toxicology, King George’s Medical University, Lucknow, Uttar Pradesh, India.

0000-0002-3272-667X

Anoop K. Verma, Department of Forensic Medicine & Toxicology, King George’s Medical University, Lucknow, Uttar Pradesh, India.

0000-0003-2446-585X

References

Morris, M. C. (2009). The role of nutrition in Alzheimer’s disease: epidemiological evidence. European Journal of Neurology, 16, 1-7.

Akingbade, O. E., & Mukaetova-Ladinska, E. B. Blood-based peripheral biomarkers for dementia: are we any closer to their use in the clinical setting?

Carr, D. B., Goate, A., Phil, D., & Morris, J. C. (1997). Current concepts in the pathogenesis of Alzheimer’s disease. The American journal of medicine, 103(3), 3S-10S.

Selkoe, D. J. (2003). Folding proteins in fatal ways. Nature, 426(6968), 900-904.

Selkoe, D. J. (2002). Alzheimer's disease is a synaptic failure. Science, 298(5594), 789-791.

Campion, D., Dumanchin, C., Hannequin, D., Dubois, B., Belliard, S., Puel, M., ... & Raux, G. (1999). Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. The American Journal of Human Genetics, 65(3), 664-670.

Brickell, K. L., Steinbart, E. J., Rumbaugh, M., Payami, H., Schellenberg, G. D., Van Deerlin, V., ... & Bird, T. D. (2006). Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease. Archives of neurology, 63(9), 1307-1311.

Kumar, A., & Singh, A. (2015). A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacological reports, 67(2), 195-203.

Nunomura, A., Honda, K., Takeda, A., Hirai, K., Zhu, X., Smith, M. A., & Perry, G. (2006). Oxidative damage to RNA in neurodegenerative diseases. Journal of Biomedicine and Biotechnology, 2006.

Sultana, R., & Butterfield, D. A. (2010). Role of oxidative stress in the progression of Alzheimer's disease. Journal of Alzheimer's Disease, 19(1), 341-353.

Bonda, D. J., Wang, X., Perry, G., Nunomura, A., Tabaton, M., Zhu, X., & Smith, M. A. (2010). Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology, 59(4-5), 290-294.

Andreyev, A. Y., Kushnareva, Y. E., & Starkov, A. A. (2005). Mitochondrial metabolism of reactive oxygen species. Biochemistry (Moscow), 70(2), 200-214.

Halliwell, B. (1992). Reactive oxygen species and the central nervous system. Journal of neurochemistry, 59(5), 1609-1623.

Kamat, P. K., Kalani, A., Rai, S., Swarnkar, S., Tota, S., Nath, C., & Tyagi, N. (2016). Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: understanding the therapeutics strategies. Molecular neurobiology, 53(1), 648-661.

Reddy, P. H., & Beal, M. F. (2008). Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends in molecular medicine, 14(2), 45-53.

Walsh, D. M., & Selkoe, D. J. (2007). Aβ oligomers–a decade of discovery. Journal of neurochemistry, 101(5), 1172-1184.

Gelain, D. P., Antonio Behr, G., Birnfeld de Oliveira, R., & Trujillo, M. (2012). Antioxidant therapies for neurodegenerative diseases: mechanisms, current trends, and perspectives.

Lyras, L., Cairns, N. J., Jenner, A., Jenner, P., & Halliwell, B. (1997). An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer's disease. Journal of neurochemistry, 68(5), 2061-2069.

Lovell, M. A., Gabbita, S. P., & Markesbery, W. R. (1999). Increased DNA oxidation and decreased levels of repair products in Alzheimer's disease ventricular CSF. Journal of neurochemistry, 72(2), 771-776.

Sayre, L. M., Smith, M. A., & Perry, G. (2001). Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Current medicinal chemistry, 8(7), 721-738.

Butterfield DA, Reed T, Sultana R. (2011) Roles of 3-nitrotyrosine- and 4-hydroxynon-enal-modified brain proteins in the progression and pathogenesis of Alzheimer’s disease. Free Radic Res, 45:59–72. doi:10.3109/10715762. 2010.520014

Krishnan, S., & Rani, P. (2014). Evaluation of selenium, redox status and their association with plasma amyloid/tau in Alzheimer’s disease. Biological trace element research, 158(2), 158-165.

Markesbery, W. R., & Lovell, M. A. (1998). Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiology of aging, 19(1), 33-36.

Jack Jr, C. R., & Holtzman, D. M. (2013). Biomarker modeling of Alzheimer’s disease. Neuron, 80(6), 1347-1358.

Saczynski, J. S., Beiser, A., Seshadri, S., Auerbach, S., Wolf, P. A., & Au, R. (2010). Depressive symptoms and risk of dementia: the Framingham Heart Study. Neurology, 75(1), 35-41.

Li, J., Wang, Y. J., Zhang, M., Xu, Z. Q., Gao, C. Y., Fang, C. Q., ... & Zhou, H. D. (2011). Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. Neurology, 76(17), 1485-1491.

Sharp, S. I., Aarsland, D., Day, S., Sønnesyn, H., Alzheimer's Society Vascular Dementia Systematic Review Group, & Ballard, C. (2011). Hypertension is a potential risk factor for vascular dementia: systematic review. International journal of geriatric psychiatry, 26(7), 661-669.

Savva, G. M., Stephan, B. C., & Alzheimer’s Society Vascular Dementia Systematic Review Group. (2010). Epidemiological studies of the effect of stroke on incident dementia: a systematic review. Stroke, 41(1), e41-e46.

Anstey, K. J., Cherbuin, N., Budge, M., & Young, J. (2011). Body mass index in midlife and late‐life as a risk factor for dementia: a meta‐analysis of prospective studies. Obesity Reviews, 12(5), e426-e437.

Plassman, B. L., Havlik, R. J., Steffens, D. C., Helms, M. J., Newman, T. N., Drosdick, D., ... & Guralnik, J. M. (2000). Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology, 55(8), 1158-1166.

Almeida, O. P., Hulse, G. K., Lawrence, D., & Flicker, L. (2002). Smoking as a risk factor for Alzheimer’s disease: contrasting evidence from a systematic review of case–control and cohort studies. Addiction, 97(1), 15-28.

Rusanen, M., Kivipelto, M., Quesenberry, C. P., Zhou, J., & Whitmer, R. A. (2011). Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia. Archives of internal medicine, 171(4), 333-339.

Lindsay, J., Laurin, D., Verreault, R., Hébert, R., Helliwell, B., Hill, G. B., & McDowell, I. (2002). Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. American journal of epidemiology, 156(5), 445-453.

Fratiglioni, L., & Wang, H. X. (2007). Brain reserve hypothesis in dementia. Journal of Alzheimer's disease, 12(1), 11-22.

Stern, C., & Munn, Z. (2010). Cognitive leisure activities and their role in preventing dementia: a systematic review. International Journal of Evidence‐Based Healthcare, 8(1), 2-17.

Li, G., Shofer, J. B., Rhew, I. C., Kukull, W. A., Peskind, E. R., McCormick, W., ... & Larson, E. B. (2010). Age‐Varying Association Between Statin Use and Incident Alzheimer's Disease: [See editorial comments by Dr. Mary Hann pp 000–000. Journal of the American Geriatrics Society, 58(7), 1311-1317.

Larrieu, S., Letenneur, L., Helmer, C., Dartigues, J. F., & Barberger-Gateau, P. (2004). Nutritional factors and risk of incident dementia in the PAQUID longitudinal cohort. Journal of Nutrition, Health & Aging.

Verreault, R., Laurin, D., Lindsay, J., & De Serres, G. (2001). Past exposure to vaccines and subsequent risk of Alzheimer's disease. Cmaj, 165(11), 1495-1498.

Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., ... & McCormack, R. (1992). Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids. Nature, 359(6393), 325-327.

Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., ... & Müller-Hill, B. (1987). The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature, 325(6106), 733-736.

Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., ... & Luo, Y. (1999). β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. science, 286(5440), 735-741.

Sastre, M., Steiner, H., Fuchs, K., Capell, A., Multhaup, G., Condron, M. M., ... & Haass, C. (2001). Presenilin‐dependent γ‐secretase processing of β‐amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO reports, 2(9), 835-841.

Yu, C., Kim, S. H., Ikeuchi, T., Xu, H., Gasparini, L., Wang, R., & Sisodia, S. S. (2001). Characterization of a Presenilin-mediated Amyloid Precursor Protein Carboxyl-terminal Fragment γ EVIDENCE FOR DISTINCT MECHANISMS INVOLVED IN γ-SECRETASE PROCESSING OF THE APP AND Notch1 TRANSMEMBRANE DOMAINS. Journal of Biological Chemistry, 276(47), 43756-43760.

Vardy, E. R., Catto, A. J., & Hooper, N. M. (2005). Proteolytic mechanisms in amyloid-β metabolism: therapeutic implications for Alzheimer's disease. Trends in molecular medicine, 11(10), 464-472.

Brown, J. (1991). Mutations in amyloid precursor protein gene and disease. Lancet (London, England), 337(8746), 923.

Hutton, M., & Hardy, J. (1997). The presenilins and Alzheimer's disease. Human molecular genetics, 6(10), 1639-1646.

Kim, H. C., Yamada, K., Nitta, A., Olariu, A., Tran, M. H., Mizuno, M., ... & Im, D. H. (2003). Immunocytochemical evidence that amyloid β (1–42) impairs endogenous antioxidant systems in vivo. Neuroscience, 119(2), 399-419.

Cutler, R. G., Kelly, J., Storie, K., Pedersen, W. A., Tammara, A., Hatanpaa, K., ... & Mattson, M. P. (2004). Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proceedings of the National Academy of Sciences, 101(7), 2070-2075.

Dikalov, S. I., Vitek, M. P., & Mason, R. P. (2004). Cupric–amyloid β peptide complex stimulates oxidation of ascorbate and generation of hydroxyl radical. Free Radical Biology and Medicine, 36(3), 340-347.

Summers, W. K. (2004). Alzheimer's disease, oxidative injury, and cytokines. Journal of Alzheimer's Disease, 6(6), 651-657.

Leduc, V., Domenger, D., De Beaumont, L., Lalonde, D., Bélanger-Jasmin, S., & Poirier, J. (2011). Function and comorbidities of apolipoprotein e in Alzheimer's disease. International Journal of Alzheimer’s Disease, 2011.

Liu, C. C., Kanekiyo, T., Xu, H., & Bu, G. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews Neurology, 9(2), 106-118.

Al Harthi, F., Huraib, G. B., Zouman, A., Arfin, M., Tariq, M., & Al-Asmari, A. (2014). Apolipoprotein E gene polymorphism and serum lipid profile in Saudi patients with psoriasis. Disease markers, 2014.

Dorey, E., Chang, N., Liu, Q. Y., Yang, Z., & Zhang, W. (2014). Apolipoprotein E, amyloid-beta, and neuroinflammation in Alzheimer’s disease. Neuroscience bulletin, 30(2), 317-330.

Sen, A., Nelson, T. J., & Alkon, D. L. (2015). ApoE4 and Aβ oligomers reduce BDNF expression via HDAC nuclear translocation. Journal of Neuroscience, 35(19), 7538-7551.

Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., ... & Small, G. W. (1994). Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature genetics, 7(2), 180-184.

Farrer, L. A., Cupples, L. A., Haines, J. L., Hyman, B., Kukull, W. A., Mayeux, R., ... & Van Duijn, C. M. (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. Jama, 278(16), 1349-1356.

Schneider, J. A., Bienias, J. L., Wilson, R. S., Berry-Kravis, E., Evans, D. A., & Bennett, D. A. (2005). The apolipoprotein E ε4 allele increases the odds of chronic cerebral infarction detected at autopsy in older persons. Stroke, 36(5), 954-959.

Ikeda, K., Akiyama, H., Arai, T., Sahara, N., Mori, H., Usami, M., ... & Takahashi, H. (1997). A subset of senile dementia with high incidence of the apolipoprotein E ϵ2 allele. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 41(5), 693-695.

Zhao, N., Liu, C. C., Qiao, W., & Bu, G. (2018). Apolipoprotein E, receptors, and modulation of Alzheimer’s disease. Biological psychiatry, 83(4), 347-357.

Maezawa, I., Nivison, M., Montine, K. S., Maeda, N., & Montine, T. J. (2006). Neurotoxicity from innate immune response is greatest with targeted replacement of ε4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK. The FASEB Journal, 20(6), 797-799.

Żekanowski, C., Styczyńska, M., Pepłońska, B., Gabryelewicz, T., Religa, D., Ilkowski, J., ... & Barczak, A. (2003). Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Experimental neurology, 184(2), 991-996.

Cruts, M., & Rademakers, R. (2007). Alzheimer disease and frontotemporal dementia mutation database [database online].

Cai, Y., An, S. S. A., & Kim, S. (2015). Mutations in presenilin 2 and its implications in Alzheimer’s disease and other dementia-associated disorders. Clinical interventions in aging, 10, 1163.

Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., ... & Wang, K. (1995). Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science, 269(5226), 973-977.

De Strooper, B., Beullens, M., Contreras, B., Levesque, L., Craessaerts, K., Cordell, B., ... & Van Leuven, F. (1997). Phosphorylation, subcellular localization, and membrane orientation of the Alzheimer's disease-associated presenilins. Journal of Biological Chemistry, 272(6), 3590-3598.

Li, J., Xu, M., Zhou, H., Ma, J., & Potter, H. (1997). Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell, 90(5), 917-927.

Sato, N., Imaizumi, K., Manabe, T., Taniguchi, M., Hitomi, J., Katayama, T., ... & Kudo, T. (2001). Increased production of β-amyloid and vulnerability to endoplasmic reticulum stress by an aberrant spliced form of presenilin 2. Journal of Biological Chemistry, 276(3), 2108-2114.

Sato, N., Hori, O., Yamaguchi, A., Lambert, J. C., Chartier‐Harlin, M. C., Robinson, P. A., ... & Tohyama, M. (1999). A novel presenilin‐2 splice variant in human Alzheimer's disease brain tissue. Journal of neurochemistry, 72(6), 2498-2505.

Leissring, M. A., Yamasaki, T. R., Wasco, W., Buxbaum, J. D., Parker, I., & LaFerla, F. M. (2000). Calsenilin reverses presenilin-mediated enhancement of calcium signaling. Proceedings of the National Academy of Sciences, 97(15), 8590-8593.

Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., ... & Kholodenko, D. (1997). Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nature medicine, 3(1), 67-72.

Bush, A. I., and Tanzi, R. E. (2008). Therapeutics for Alzheimer’s disease based on the metal hypothesis. Neurotherapeutics 5, 421–432. doi: 10.1016/j.nurt.2008. 05.001

Ayton, S., Lei, P., & Bush, A. I. (2015). Biometals and their therapeutic implications in Alzheimer’s disease. Neurotherapeutics, 12(1), 109-120.

Bush, A. I. (2003). The metallobiology of Alzheimer's disease. Trends in neurosciences, 26(4), 207-214.

Chowdhury, B. A., & Chandra, R. K. (1987). Biological and health implications of toxic heavy metal and essential trace element interactions. Progress in food & nutrition science, 11(1), 55.

Leal, S. S., Botelho, H. M., & Gomes, C. M. (2012). Metal ions as modulators of protein conformation and misfolding in neurodegeneration. Coordination Chemistry Reviews, 256(19-20), 2253-2270.

Pfaender, S., & Grabrucker, A. M. (2014). Characterization of biometal profiles in neurological disorders. Metallomics, 6(5), 960-977.

Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L., & Markesbery, W. R. (1998). Copper, iron and zinc in Alzheimer's disease senile plaques. Journal of the neurological sciences, 158(1), 47-52.

Zatta, P., Drago, D., Bolognin, S., & Sensi, S. L. (2009). Alzheimer's disease, metal ions and metal homeostatic therapy. Trends in Pharmacological Sciences, 30(7), 346-355.

Breydo, L., & Uversky, V. N. (2011). Role of metal ions in aggregation of intrinsically disordered proteins in neurodegenerative diseases. Metallomics, 3(11), 1163-1180.

Droge, W., and Schipper, H. M. (2007). Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell 6, 361–370. doi: 10.1111/j.1474-9726. 2007.00294.x

Muhoberac, B. B., and Vidal, R. (2013). Abnormal iron homeostasis and neurodegeneration. Front. Aging Neurosci. 5:32. doi: 10.3389/fnagi.2013. 00032 9866–9868, 1997.

Smith, M. A., Harris, P. L., Sayre, L. M., & Perry, G. (1997). Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proceedings of the National Academy of Sciences, 94(18), 9866-9868.

Plascencia-Villa, G., Ponce, A., Collingwood, J. F., Arellano-Jiménez, M. J., Zhu, X., Rogers, J. T., ... & Perry, G. (2016). High-resolution analytical imaging and electron holography of magnetite particles in amyloid cores of Alzheimer’s disease. Scientific reports, 6, 24873.

Bodovitz, S., Falduto, M. T., Frail, D. E., and Klein, W. L. (1995). Iron levels modulate alpha-secretase cleavage of amyloid precursor protein. J. Neurochem. 64, 307–315. doi: 10.1046/j.1471-4159.1995.64010307.x

Crielaard, B. J., Lammers, T., and Rivella, S. (2017). Targeting iron metabolism in drug discovery and delivery. Nat. Rev. Drug Discov. 16, 400–423. doi: 10.1038/ nrd.2016.248

Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R., and Zecca, L. (2014). The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 13, 1045–1060. doi: 10.1016/S1474-4422(14)70117-6

Jiang, H., Wang, J., Rogers, J., and Xie, J. (2017). Brain iron metabolism dysfunction in Parkinson’s disease. Mol. Neurobiol. 54, 3078–3101. doi: 10.1007/s12035- 016-9879-1

Rogers, J. T., Randall, J. D., Cahill, C. M., Eder, P. S., Huang, X., Gunshin, H., et al. (2002). An iron-responsive element type II in the 50-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J. Biol. Chem. 277, 45518–45528. doi: 10.1074/jbc.M207435200

Gerlach, M., Ben-Shachar, D., Riederer, P., and Youdim, M. B. (1994). Altered brain metabolism of iron as a cause of neurodegenerative diseases? J. Neurochem. 63, 793–807. doi: 10.1046/j.1471-4159.1994.63030793.

Rodrigue, K. M., Haacke, E. M., and Raz, N. (2011). Differential effects of age and history of hypertension on regional brain volumes and iron. Neuroimage 54, 750–759. doi: 10.1016/j.neuroimage.2010.09.068

Collingwood, J. F., and Davidson, M. R. (2014). The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light. Front. Pharmacol. 5:191. doi: 10.3389/fphar.2014.00191

Ramos, P., Santos, A., Pinto, N. R., Mendes, R., Magalhaes, T., and Almeida, A. (2014). Iron levels in the human brain: a post-mortem study of anatomical region differences and age-related changes. J. Trace Elem. Med. Biol. 28, 13–17. doi: 10.1016/j.jtemb.2013.08.001

Zatta, P., and Frank, A. (2007). Copper deficiency and neurological disorders in man and animals. Brain Res. Rev. 54, 19–33. doi: 10.1016/j.brainresrev.2006. 10.001

Desai, V., and Kaler, S. G. (2008). Role of copper in human neurological disorders. Am. J. Clin. Nutr. 88, 855S–858S.

Scheiber, I. F., and Dringen, R. (2013). Astrocyte functions in the copper homeostasis of the brain. Neurochem. Int. 62, 556–565. doi: 10.1016/j.neuint. 2012.08.017

Klevay, L. M. (2008). Alzheimer’s disease as copper deficiency. Med. Hypotheses 70, 802–807. doi: 10.1016/j.mehy.2007.04.051

Vaz, F. N. C., Fermino, B. L., Haskel, M. V. L., Wouk, J., de Freitas, G. B. L., Fabbri, R., et al. (2017). The relationship between copper, iron, and selenium levels and Alzheimer disease. Biol. Trace Elem. Res. doi: 10.1007/s12011-017-1042-y [Epub ahead of print]

Su, X. Y., Wu, W. H., Huang, Z. P., Hu, J., Lei, P., Yu, C. H., et al. (2007). Hydrogen peroxide can be generated by tau in the presence of Cu (II). Biochem. Biophys. Res. Commun. 358, 661–665. doi: 10.1016/j.bbrc.2007.04.191

Kitazawa, M., Cheng, D., and Laferla, F. M. (2009). Chronic copper exposure exacerbates both amyloid and tau pathology and selectively dysregulates cdk5 in a mouse model of AD. J. Neurochem. 108, 1550–1560. doi: 10.1111/j.1471- 4159.2009.05901.x

Acevedo, K. M., Hung, Y. H., Dalziel, A. H., Li, Q. X., Laughton, K., Wikhe, K., et al. (2011). Copper promotes the trafficking of the amyloid precursor protein. J. Biol. Chem. 286, 8252–8262. doi: 10.1074/jbc.M110.128512

Barr, C. A., and Burdette, S. C. (2017). The zinc paradigm for metalloneurochemistry. Essays Biochem. 61, 225–235. doi: 10.1042/ EBC20160073

Takeda, A. (2001). Zinc homeostasis and functions of zinc in the brain. Biometals, 14(3-4), 343-351.

Lovell, M. A., Smith, J. L., & Markesbery, W. R. (2006). Elevated zinc transporter-6 in mild cognitive impairment, Alzheimer disease, and pick disease. Journal of Neuropathology & Experimental Neurology, 65(5), 489-498.

Palmiter, R. D., & Findley, S. D. (1995). Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. The EMBO journal, 14(4), 639-649.

Swardfager, W., Herrmann, N., McIntyre, R. S., Mazereeuw, G., Goldberger, K., Cha, D. S., et al. (2013). Potential roles of zinc in the pathophysiology and treatment of major depressive disorder. Neurosci. Biobehav. Rev. 37, 911–929. doi: 10.1016/j.neubiorev.2013.03.018

Danscher, G., Jensen, K. B., Frederickson, C. J., Kemp, K., Andreasen, A., Juhl, S., ... & Ravid, R. (1997). Increased amount of zinc in the hippocampus and amygdala of Alzheimer's diseased brains: a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material. Journal of neuroscience methods, 76(1), 53-59.

Frederickson, C. J., Suh, S. W., Silva, D., Frederickson, C. J., & Thompson, R. B. (2000). Importance of zinc in the central nervous system: the zinc-containing neuron. The Journal of nutrition, 130(5), 1471S-1483S.

Jo, S. M., Won, M. H., Cole, T. B., Jensen, M. S., Palmiter, R. D., & Danscher, G. (2000). Zinc-enriched (ZEN) terminals in mouse olfactory bulb. Brain research, 865(2), 227-236.

Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L., & Markesbery, W. R. (1998). Copper, iron and zinc in Alzheimer's disease senile plaques. Journal of the neurological sciences, 158(1), 47-52.

Lee, J. Y., Cole, T. B., Palmiter, R. D., Suh, S. W., & Koh, J. Y. (2002). Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proceedings of the National Academy of Sciences, 99(11), 7705-7710.

Miller, Y., Ma, B., & Nussinov, R. (2010). Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states. Proceedings of the National Academy of Sciences, 107(21), 9490-9495.

Antala, S., and Dempski, R. E. (2012). The human ZIP4 transporter has two distinct binding affinities and mediates transport of multiple transition metals. Biochemistry 51, 963–973. doi: 10.1021/bi201553p

Multhaup, G., Bush, A. I., Pollwein, P., & Masters, C. L. (1994). Interaction between the zinc (II) and the heparin binding site of the Alzheimer's disease βA4 amyloid precursor protein (APP). FEBS letters, 355(2), 151-154.

Multhaup, G., Ruppert, T., Schlicksupp, A., Hesse, L., Bill, E., Pipkorn, R., ... & Beyreuther, K. (1998). Copper-binding amyloid precursor protein undergoes a site-specific fragmentation in the reduction of hydrogen peroxide. Biochemistry, 37(20), 7224-7230.

Hoke, D. E., Tan, J. L., Ilaya, N. T., Culvenor, J. G., Smith, S. J., White, A. R., et al. (2005). In vitro gamma-secretase cleavage of the Alzheimer’s amyloid precursor protein correlates to a subset of presenilin complexes and is inhibited by zinc. FEBS J. 272, 5544–5557. doi: 10.1111/j.1742-4658.2005.04950.x

Religa, D., Strozyk, D., Cherny, R. A., Volitakis, I., Haroutunian, V., Winblad, B., et al. (2006). Elevated cortical zinc in Alzheimer disease. Neurology 67, 69–75. doi: 10.1212/01.wnl.0000223644.08653.b5

Hozumi, I., Hasegawa, T., Honda, A., Ozawa, K., Hayashi, Y., Hashimoto, K., et al. (2011). Patterns of levels of biological metals in CSF differ among neurodegenerative diseases. J. Neurol. Sci. 303, 95–99. doi: 10.1016/j.jns.2011. 01.003

Yoshiike, Y., Tanemura, K., Murayama, O., Akagi, T., Murayama, M., Sato, S., et al. (2001). New insights on how metals disrupt amyloid beta-aggregation and their effects on amyloid-beta cytotoxicity. J. Biol. Chem. 276, 32293–32299. doi: 10.1074/jbc.M010706200

Crapper, D. R., Krishnan, S. S., and Dalton, A. J. (1973). Brain aluminum distribution in Alzheimers disease and experimental neurofibrillary degeneration. Science 180, 511–513.

Fattoretti, P., Bertoni-Freddari, C., Balietti, M., Giorgetti, B., Solazzi, M., and Zatta, P. (2004). Chronic aluminum administration to old rats results in increased levels of brain metal ions and enlarged hippocampal mossy fibers. Ann. N. Y. Acad. Sci. 1019, 44–47. doi: 10.1196/annals.1297.010

Exley, C., Price, N. C., Kelly, S. M., and Birchall, J. D. (1993). An interaction of beta-amyloid with aluminium in vitro. FEBS Lett. 324, 293–295.

Kawahara, M., Kato, M., and Kuroda, Y. (2001). Effects of aluminum on the neurotoxicity of primary cultured neurons and on the aggregation of betaamyloid protein. Brain Res. Bull. 55, 211–217.

Sato, N., Hori, O., Yamaguchi, A., Lambert, J. C., Chartier-Harlin, M. C., Robinson, P. A., et al. (1999). A novel presenilin-2 splice variant in human Alzheimer’s disease brain tissue. J. Neurochem. 72, 2498–2505.

Exley, C., Price, N. C., Kelly, S. M., & Birchall, J. D. (1993). An interaction of β‐amyloid with aluminium in vitro. FEBS letters, 324(3), 293-295.

Kawahara, M. (2010). Role of calcium dyshomeostasis via amyloid channels in the pathogenesis of Alzheimer’s disease. Current Pharmaceutical Design, 16, 2779-2789.

Mantyh, P. W., Ghilardi, J. R., Rogers, S., DeMaster, E., Allen, C. J., Stimson, E. R., & Maggio, J. E. (1993). Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of β‐amyloid peptide. Journal of neurochemistry, 61(3), 1171-1174.

Chong, Y. H., & Suh, Y. H. (1995). Aggregation of amyloid precursor proteins by aluminum in vitro. Brain research, 670(1), 137-141.

Muma, N. A., & Singer, S. M. (1996). Aluminum-induced neuropathology: transient changes in microtubule-associated proteins. Neurotoxicology and teratology, 18(6), 679-690.

El‐Sebae, A. H., Abdel‐Ghanv, M. E., Shalloway, D., Zeid, M. A., Blancato, J., & Saleh, M. A. (1993). Aluminum interaction with human brain tau protein phosphorylation by various kinases. Journal of Environmental Science & Health Part B, 28(6), 763-777.

Murayama, H., Shin, R. W., Higuchi, J., Shibuya, S., Muramoto, T., & Kitamoto, T. (1999). Interaction of aluminum with PHFτ in Alzheimer's disease neurofibrillary degeneration evidenced by desferrioxamine-assisted chelating autoclave method. The American journal of pathology, 155(3), 877-885.

Johnson, V. J., & Sharma, R. P. (2003). Aluminum disrupts the pro-inflammatory cytokine/neurotrophin balance in primary brain rotation-mediated aggregate cultures: possible role in neurodegeneration. Neurotoxicology, 24(2), 261-268.

Yamamoto, H., Saitoh, Y., Yasugawa, S., & Miyamoto, E. (1990). Dephosphorylation of r factor by protein phosphatase 2A in synaptosomal cytosol fractions, and inhibition by aluminum. Journal of neurochemistry, 55(2), 683-690.

Oteiza, P. I. (1994). A mechanism for the stimulatory effect of aluminum on iron-induced lipid peroxidation. Archives of Biochemistry and Biophysics, 308(2), 374-379.

Martyn, C. N., Osmond, C., Edwardson, J. A., Barker, D. J. P., Harris, E. C., & Lacey, R. F. (1989). Geographical relation between Alzheimer's disease and aluminium in drinking water. The Lancet, 333(8629), 59-62.

Flaten TP. (1990) Geographical associations between aluminium in drinking water and death rates with dementia (including Alzheimer’s disease), Parkinson’s disease and amyotrophic lateral sclerosis in Norway. Environ Geochem Health, 12:152–67.

McLachlan, D. R. C., Bergeron, C., Smith, J. E., Boomer, D., & Rifat, S. L. (1996). Risk for neuropathologically confirmed Alzheimer's disease and residual aluminum in municipal drinking water employing weighted residential histories. Neurology, 46(2), 401-405.

Mirza A, King A, Troakes C, Exley C (2016) The identification of aluminum in human brain tissue using lumogallion and fluorescence microscopy. J Alzheimers Dis 54, 1333-1338.

Exley C, Esiri MM (2006) Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK. J Neurol Neurosurg Psychiatry 77, 877-879.

Exley C, Vickers T (2014) Elevated brain aluminium and early onset Alzheimer’s disease in an individual occupationally exposed to aluminium: A case report. J Med Case Rep 8, 41.

Bellinger DC (2008) Very low lead exposures and children’s neurodevelopment. Curr Opin Pediatr 20, 172–177. [PubMed: 18332714]

Lidsky TI, Schneider JS (2003) Lead neurotoxicity in children: Basic mechanisms and clinical correlates. Brain 126, 5–19. [PubMed: 12477693]

Mason LH, Harp JP, Han DY (2014) Pb neurotoxicity: Neuropsychological effects of lead toxicity. BioMed Res Int 2014, 1–8.

Weisskopf, M. G., Proctor, S. P., Wright, R. O., Schwartz, J., Spiro III, A., Sparrow, D., ... & Hu, H. (2007). Cumulative lead exposure and cognitive performance among elderly men. Epidemiology, 59-66.

Power, M. C., Korrick, S., Tchetgen, E. J. T., Nie, L. H., Grodstein, F., Hu, H., ... & Weisskopf, M. G. (2014). Lead exposure and rate of change in cognitive function in older women. Environmental research, 129, 69-75.

Shih, R. A., Glass, T. A., Bandeen-Roche, K., Carlson, M. C., Bolla, K. I., Todd, A. C., & Schwartz, B. S. (2006). Environmental lead exposure and cognitive function in community-dwelling older adults. Neurology, 67(9), 1556-1562.

van Wijngaarden, E., Winters, P. C., & Cory-Slechta, D. A. (2011). Blood lead levels in relation to cognitive function in older US adults. Neurotoxicology, 32(1), 110-115.

Lefauconnier JM, Bernard G, Mellerio F, Sebille A, Cesarini E (1983) Lead distribution in the nervous system of 8-month-old rats intoxicated since birth by lead. Experientia 39, 1030–1031. [PubMed: 6884491]

Grandjean P (1978) Regional distribution of lead in human brains. Toxicol Lett 2, 65–69.

Haraguchi T, Ishizu H, Takehisa Y, Kawai K, Yokota O, Terada S, Tsuchiya K, Ikeda K, Morita K, Horike T, Kira S, Kuroda S (2001) Lead content of brain tissue in diffuse neurofibrillary tangles with calcification (DNTC): The possibility of lead neurotoxicity. Neuroreport 12, 3887–3890. [PubMed: 11742204]

Dosunmu R, Alashwal H, Zawia NH (2012) Genome-wide expression and methylation profiling in the aged rodent brain due to early-life Pb exposure and its relevance to aging. Mech Ageing Dev 133, 435–443. [PubMed: 22613225]

Huang H, Bihaqi SW, Cui L, Zawia NH (2011) In vitro Pb exposure disturbs the balance between Aβ production and elimination: The role of AβPP and neprilysin. Neurotoxicology 32, 300–306. [PubMed: 21315759]

Hernández-Avila, M., Smith, D., Meneses, F., Sanin, L. H., & Hu, H. (1998). The influence of bone and blood lead on plasma lead levels in environmentally exposed adults. Environmental health perspectives, 106(8), 473-477.

Rabinowitz, M. B., Wetherill, G. W., & Kopple, J. D. (1976). Kinetic analysis of lead metabolism in healthy humans. The Journal of Clinical Investigation, 58(2), 260-270.

Hu, H., Aro, A., & Rotnitzky, A. (1995). Bone lead measured by X-ray fluorescence: epidemiologic methods. Environmental Health Perspectives, 103(suppl 1), 105-110.

Chettle, D. R. (2005). Three decades of in vivo x‐ray fluorescence of lead in bone. X‐Ray Spectrometry: An International Journal, 34(5), 446-450.

Garcia, F., Ortega, A., Domingo, J. L., & Corbella, J. (2001). Accumulation of metals in autopsy tissues of subjects living in Tarragona County, Spain. Journal of Environmental Science and Health, Part A, 36(9), 1767-1786.

Basha, M. R., Murali, M., Siddiqi, H. K., Ghosal, K., Siddiqi, O. K., Lashuel, H. A., ... & Zawia, N. H. (2005). Lead (Pb) exposure and its effect on APP proteolysis and Aβ aggregation. The FASEB Journal, 19(14), 2083-2084.

Basha, M. R., Wei, W., Bakheet, S. A., Benitez, N., Siddiqi, H. K., Ge, Y. W., ... & Zawia, N. H. (2005). The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and β-amyloid in the aging brain. Journal of Neuroscience, 25(4), 823-829.

Smedley, P.L., and Kinniburgh, D.G. (2002). A review of the source, behaviour and distribution of arsenic in natural waters, Applied Geochemistry 17, 517-568

Tyler CR, Allan AM (2014) The Effects of Arsenic Exposure on Neurological and Cognitive Dysfunction in Human and Rodent Studies: A Review. Curr Environ Health Rep 1: 132–147. PMID: 24860722

Dani, S.U. (2010). Arsenic for the fool: An exponential connection. Sci Total Environ 408, 1842-6.

Sanchez-Pena, L. C., Petrosyan, P., Morales, M., Gonzalez, N. B., Gutiérrez-Ospina, G., Del Razo, L. M., & Gonsebatt, M. E. (2010). Arsenic species, AS3MT amount, and AS3MT gene expression in different brain regions of mouse exposed to arsenite. Environmental research, 110(5), 428-434.

Smith, A. H., Lopipero, P. A., Bates, M. N., & Steinmaus, C. M. (2002). Arsenic epidemiology and drinking water standards.

Gailer, J. (2009). Chronic toxicity of AsIII in mammals: the role of (GS) 2AsSe−. Biochimie, 91(10), 1268-1272.

Rodrıguez, V. M., Carrizales, L., Mendoza, M. S., Fajardo, O. R., & Giordano, M. (2002). Effects of sodium arsenite exposure on development and behavior in the rat. Neurotoxicology and teratology, 24(6), 743-750.

Rahman, M., Tondel, M., Ahmad, S. A., & Axelson, O. (1998). Diabetes mellitus associated with arsenic exposure in Bangladesh. American Journal of epidemiology, 148(2), 198-203.

Morton, W. E., & Caron, G. A. (1989). Encephalopathy: an uncommon manifestation of workplace arsenic poisoning?. American journal of industrial medicine, 15(1), 1-5.

Chou CT, Lin WF, Kong ZL, Chen SY, Hwang DF (2013) Taurine prevented cell cycle arrest and restored neurotrophic gene expression in arsenite-treated SH-SY5Y cells. Amino Acids 45: 811–819. doi: 10.1007/s00726-013-1524-y PMID: 23744399

Huo TG, Li WK, Zhang YH, Yuan J, Gao LY, et al. (2014) Excitotoxicity Induced by Realgar in the Rat Hippocampus: the Involvement of Learning Memory Injury, Dysfunction of Glutamate Metabolism and NMDA Receptors. Mol Neurobiol.

Niño, S.A., Martel-Gallegos, G., Castro-Zavala, A., Ortega-Berlanga, B.,Delgado, J.M., Hernández-Mendoza, H. Romero-Guzmán E., Ríos-Lugo J.,Rosales-Mendoza S., Jiménez-Capdeville M.E., and Zarazúa, S. (2018). Chronic Arsenic Exposure Increases Aβ (1–42) Production and Receptor for Advanced Glycation End Products Expression in Rat Brain, Chem Res Toxicol 31, 13-21

ATSDR, “GuidanceManual for the Joint Toxic Action of Chemical Mixtures,” 2004, http://www.atsdr.cdc.gov/interactionprofiles/ ipga.html.

Cao, Y., Chen, A., Radcliffe, J., Dietrich, K. N., Jones, R. L., Caldwell, K., & Rogan, W. J. (2009). Postnatal cadmium exposure, neurodevelopment, and blood pressure in children at 2, 5, and 7 years of age. Environmental health perspectives, 117(10), 1580-1586.

Tjälve, H., & Henriksson, J. (1999). Uptake of metals in the brain via olfactory pathways. Neurotoxicology, 20(2-3), 181-195.

Fern, R. O. B. E. R. T., Black, J. A., Ransom, B. R., & Waxman, S. G. (1996). Cd (2+)-induced injury in CNS white matter. Journal of Neurophysiology, 76(5), 3264-3273.

Viaene, M. K., Masschelein, R., Leenders, J., De Groof, M., Swerts, L. J. V. C., & Roels, H. A. (2000). Neurobehavioural effects of occupational exposure to cadmium: a cross sectional epidemiological study. Occupational and environmental medicine, 57(1), 19-27.

Jiang, L. F., Yao, T. M., Zhu, Z. L., Wang, C., & Ji, L. N. (2007). Impacts of Cd (II) on the conformation and self-aggregation of Alzheimer's tau fragment corresponding to the third repeat of microtubule-binding domain. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics, 1774(11), 1414-1421.

Yuan, Y., Jiang, C. Y., Xu, H., Sun, Y., Hu, F. F., Bian, J. C., ... & Liu, Z. P. (2013). Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway. PloS one, 8(5), e64330

M. M´endez-Armenta, J. Villeda-Hern´andez, R. Barroso- Moguel, C. Nava-Ru´ız, M. E. Jim´enez-Capdeville, and C. R´ıos, (2003). Brain regional lipid peroxidation and metallothionein levels of developing rats exposed to cadmium and dexamethasone. Toxicology Letters, vol, 144, no. 2, pp. 151–157.

Chen, L., Liu, L., & Huang, S. (2008). Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5. Free Radical Biology and Medicine, 45(7), 1035-1044.

Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1:11-21.

Mezynska, M., & Brzoska, M. M. (2018). Environmental exposure to cadmium—A risk for health of the general population in industrialized countries and preventive strategies. Environmental Science and Pollution Research, 25(4), 3211-3232.

Tamás, M. J., Fauvet, B., Christen, P., & Goloubinoff, P. (2018). Misfolding and aggregation of nascent proteins: a novel mode of toxic cadmium action in vivo. Current genetics, 64(1), 177-181.

Saturnino, C., Iacopetta, D., Sinicropi, M. S., Rosano, C., Caruso, A., Caporale, A., ... & Longo, P. (2014). N-alkyl carbazole derivatives as new tools for Alzheimer’s disease: preliminary studies. Molecules, 19(7), 9307-9317.

Chen, Y. Y., Zhu, J. Y., & Chan, K. M. (2014). Effects of cadmium on cell proliferation, apoptosis, and proto-oncogene expression in zebrafish liver cells. Aquatic toxicology, 157, 196-206.

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.

Bjørklund, G., Dadar, M., Mutter, J., & Aaseth, J. (2017). The toxicology of mercury: Current research and emerging trends. Environmental research, 159, 545-554.

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

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.

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.

Myrtd, G.J., Davidson, P.W., Cox, C., Shamlaye, C.F., Palumbo, D., Cernichiari, E., Sloane-Reeves, J., Wilding, G.E., Kost, J., Huang, L.S. and Clarkson, T.W. (2003) Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study. Lancet, 361, 1686- 1692.

Olivieri, G., Novakovic, M., Savaskan, E., Meier, F., Baysang, G., Brockhaus, M. and Müller-Spahn, F. (2002) The effects of beta-estradiol on SHSY5Y neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and beta-amyloid secretion. Neuroscience, 113, 849-855.

Clarkson, T.W. (1993) Mercury: major issues in environmental health. Environ. Health Perspect., 100, 31-38.

Ehmann, W.D., Markesbery, W.R., Alauddin, M., Hossain, T.I. and Brubaker, E.H. (1986) Brain trace elements in Alzheimer’s disease. Neurotoxicology, 7, 195-206.

Perkins, A. J., Hendrie, H. C., Callahan, C. M., Gao, S., Unverzagt, F. W., Xu, Y., ... & Hui, S. L. (1999). Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey. American journal of epidemiology, 150(1), 37-44.

Engelhart, M. J., Geerlings, M. I., Ruitenberg, A., van Swieten, J. C., Hofman, A., Witteman, J. C., & Breteler, M. M. (2002). Dietary intake of antioxidants and risk of Alzheimer disease. Jama, 287(24), 3223-3229.

Sen, C. K., Khanna, S., Roy, S., & Packer, L. (2000). Molecular Basis of Vitamin E Action Tocotrienol potently inhibits glutamate-induced pp60c-Src Kinase activation and death of ht4 neuronal cells. Journal of Biological Chemistry, 275(17), 13049-13055.

Meister A. (1994) Glutathione, ascorbate, and cellular protection. Cancer Res ,54:1969s–1975s. [PubMed: 8137322]

Sies, H., & Stahl, W. (1995). Vitamins E and C, beta-carotene, and other carotenoids as antioxidants. The American journal of clinical nutrition, 62(6), 1315S-1321S.

Anderson, R., Ramafi, G., & Theron, A. J. (1996). Membrane stabilizing, anti-oxidative interactions of propranolol and dexpropranolol with neutrophils. Biochemical pharmacology, 52(2), 341-349.

Yadav, J., Verma, A. K., Garg, R. K., Ahmad, K., Mahdi, A. A., & Srivastava, S. (2020). Sialic acid associated with oxidative stress and total antioxidant capacity (TAC) expression level as a predictive indicator in moderate to severe Alzheimer's disease. Experimental Gerontology, 111092.

Rodriguez-Casado, A. (2016). The health potential of fruits and vegetables phytochemicals: notable examples. Critical Reviews in Food Science and Nutrition, 56(7), 1097-1107.

Montiel, T., Quiroz-Baez, R., Massieu, L., & Arias, C. (2006). Role of oxidative stress on β-amyloid neurotoxicity elicited during impairment of energy metabolism in the hippocampus: Protection by antioxidants. Experimental neurology, 200(2), 496-508.

Devore, E. E., Grodstein, F., van Rooij, F. J., Hofman, A., Stampfer, M. J., Witteman, J. C., & Breteler, M. M. (2010). Dietary antioxidants and long-term risk of dementia. Archives of neurology, 67(7), 819-825.

Regland, B., Gottfries, C. G., & Oreland, L. (1991). Vitamin B 12-induced reduction of platelet monoamine oxidase activity in patients with dementia and pernicious anaemia. European archives of psychiatry and clinical neuroscience, 240(4-5), 288-291.

Lim, G. P., Chu, T., Yang, F., Beech, W., Frautschy, S. A., & Cole, G. M. (2001). The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. Journal of Neuroscience, 21(21), 8370-8377.

Terada, A., Yoshida, M., Seko, Y., Kobayashi, T., Yoshida, K., Nakada, M., ... & Rikihisa, T. (1999). Active oxygen species generation and cellular damage by additives of parenteral preparations: selenium and sulfhydryl compounds. Nutrition, 15(9), 651-655.