{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T20:16:49Z","timestamp":1788812209976,"version":"build-2803163510"},"reference-count":71,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T00:00:00Z","timestamp":1696550400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sao Paulo State Foundation","award":["2020\/14175-0"],"award-info":[{"award-number":["2020\/14175-0"]}]},{"name":"Sao Paulo State Foundation","award":["307856\/2021-6"],"award-info":[{"award-number":["307856\/2021-6"]}]},{"name":"Sao Paulo State Foundation","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"multiuser central facilities (UFABC)","award":["2020\/14175-0"],"award-info":[{"award-number":["2020\/14175-0"]}]},{"name":"multiuser central facilities (UFABC)","award":["307856\/2021-6"],"award-info":[{"award-number":["307856\/2021-6"]}]},{"name":"multiuser central facilities (UFABC)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior-Brasil (CAPES)","award":["2020\/14175-0"],"award-info":[{"award-number":["2020\/14175-0"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior-Brasil (CAPES)","award":["307856\/2021-6"],"award-info":[{"award-number":["307856\/2021-6"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior-Brasil (CAPES)","award":["001"],"award-info":[{"award-number":["001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>It is undeniable that as people get older, they become progressively more susceptible to neurodegenerative illnesses such as Alzheimer\u2019s disease (AD). Memory loss is a prominent symptom of this condition and can be exacerbated by uneven levels of certain metals. This study used inductively coupled plasma mass spectrometry (ICP-MS) to examine the levels of metals in the blood plasma, frontal cortex, and hippocampus of Wistar rats with AD induced by streptozotocin (STZ). It also tested the effects of the antioxidant hydroxytyrosol (HT) on metal levels. The Barnes maze behavior test was used, and the STZ group showed less certainty and greater distance when exploring the Barnes maze than the control group. The results also indicated that the control group and the STZ + HT group exhibited enhanced learning curves during the Barnes maze training as compared to the STZ group. The ICP-MS analysis showed that the STZ group had lower levels of cobalt in their blood plasma than the control group, while the calcium levels in the frontal cortex of the STZ + HT group were higher than in the control group. The most important finding was that copper levels in the frontal cortex from STZ-treated animals were higher than in the control group, and that the STZ + HT group returned to equivalent levels to the control group. The antioxidant HT can restore copper levels to their basal physiological state. This finding may help explain HT\u2019s potential beneficial effect in AD-patients.<\/jats:p>","DOI":"10.3390\/ijms241914950","type":"journal-article","created":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T07:49:29Z","timestamp":1696578569000},"page":"14950","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The Impact of Hydroxytyrosol on the Metallomic-Profile in an Animal Model of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"given":"Miguel","family":"Tabanez","sequence":"first","affiliation":[{"name":"Center for Natural Sciences and Humanities, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"},{"name":"Metal Biochemistry and Oxidative Stress Laboratory, Center for Natural Sciences and Humanities, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilma","family":"Santos","sequence":"additional","affiliation":[{"name":"Center for Natural Sciences and Humanities, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"},{"name":"Metal Biochemistry and Oxidative Stress Laboratory, Center for Natural Sciences and Humanities, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Ikebara","sequence":"additional","affiliation":[{"name":"Center for Mathematics, Computing and Cognition, Federal University of ABC, S\u00e3o Bernardo do Campo 09606-045, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Camargo","sequence":"additional","affiliation":[{"name":"Center for Natural Sciences and Humanities, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"},{"name":"Metal Biochemistry and Oxidative Stress Laboratory, Center for Natural Sciences and Humanities, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Dos Santos","sequence":"additional","affiliation":[{"name":"Center for Mathematics, Computing and Cognition, Federal University of ABC, S\u00e3o Bernardo do Campo 09606-045, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5639-1552","authenticated-orcid":false,"given":"Bruna","family":"Freire","sequence":"additional","affiliation":[{"name":"Center for Natural Sciences and Humanities, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2216-9013","authenticated-orcid":false,"given":"Bruno","family":"Batista","sequence":"additional","affiliation":[{"name":"Center for Natural Sciences and Humanities, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Takada","sequence":"additional","affiliation":[{"name":"Center for Mathematics, Computing and Cognition, Federal University of ABC, S\u00e3o Bernardo do Campo 09606-045, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5624-1140","authenticated-orcid":false,"given":"Rosanna","family":"Squitti","sequence":"additional","affiliation":[{"name":"Department of Laboratory Science, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Kihara","sequence":"additional","affiliation":[{"name":"Center for Mathematics, Computing and Cognition, Federal University of ABC, S\u00e3o Bernardo do Campo 09606-045, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8606-5400","authenticated-orcid":false,"given":"Giselle","family":"Cerchiaro","sequence":"additional","affiliation":[{"name":"Center for Natural Sciences and Humanities, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"},{"name":"Metal Biochemistry and Oxidative Stress Laboratory, Center for Natural Sciences and Humanities, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,6]]},"reference":[{"key":"ref_1","first-page":"810","article-title":"Effect of nutrition on neurodegenerative diseases. A systematic review","volume":"4","author":"Bianchi","year":"2019","journal-title":"Nutr. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.mito.2020.08.003","article-title":"Mitochondrial abnormalities in neurodegenerative models and possible interventions: Focus on Alzheimer\u2019s disease, Parkinson\u2019s disease, Huntington\u2019s disease","volume":"55","author":"Pantiya","year":"2020","journal-title":"Mitochondrion"},{"key":"ref_3","unstructured":"International AD (2021, January 03). Numbers of People with Dementia around the World. Dementia Statistics. Available online: https:\/\/www.alzint.org\/resource\/numbers-of-people-with-dementia-worldwide\/."},{"key":"ref_4","first-page":"1170","article-title":"A Comprehensive Review on Alzheimer\u2019s Disease","volume":"10","author":"Anwal","year":"2021","journal-title":"World J. Pharm. Pharm. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.expneurol.2009.09.014","article-title":"A\u03b2 exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer\u2019s disease","volume":"223","author":"Folwell","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fnagi.2019.00034","article-title":"Pathological Tau from Alzheimer\u2019s Brain Induces Site-Specific Hyperphosphorylation and SDS- and Reducing Agent-Resistant Aggregation of Tau in vivo","volume":"11","author":"Miao","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3389\/fnagi.2020.00265","article-title":"Mechanisms of Pathogenic Tau and A\u03b2 Protein Spreading in Alzheimer\u2019s Disease","volume":"12","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1002\/ana.20854","article-title":"Mediterranean diet and risk for Alzheimer\u2019s disease","volume":"59","author":"Scarmeas","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3233\/JAD-130830","article-title":"Association of Mediterranean diet with mild cognitive impairment and Alzheimer\u2019s disease: A systematic review and meta-analysis","volume":"39","author":"Singh","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1016\/j.nut.2009.11.009","article-title":"More than the sum of its parts? Nutrition in Alzheimer\u2019s disease","volume":"26","author":"Gola","year":"2010","journal-title":"Nutrition"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"741444","DOI":"10.3389\/fchem.2021.741444","article-title":"Novel Hydroxytyrosol-Donepezil Hybrids as Potential Antioxidant and Neuroprotective Agents","volume":"9","author":"Costanzo","year":"2021","journal-title":"Front. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Karkovi, A., and Barbari, M. (2019). Potential Effects on Human Health. Molecules, 24.","DOI":"10.3390\/molecules24102001"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.redox.2016.10.006","article-title":"Hydroxytyrosol inhibits hydrogen peroxide-induced apoptotic signaling via labile iron chelation","volume":"10","author":"Kitsati","year":"2016","journal-title":"Redox Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5181","DOI":"10.1021\/jf980649b","article-title":"Effect of Hydroxytyrosol Found in Extra Virgin Olive Oil on Oxidative DNA Damage and on Low-Density Lipoprotein Oxidation","volume":"46","author":"Aruoma","year":"1998","journal-title":"J. Agric. Food Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3738","DOI":"10.1021\/jf060033j","article-title":"Effects of copper on the antioxidant activity of olive polyphenols in bulk oil and oil-in-water emulsions","volume":"54","author":"Santos","year":"2006","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-P\u00e9rez, M.D., L\u00f3pez-Villodres, J.A., Arrebola, M.M., Mart\u00edn-Aurioles, E., Fern\u00e1ndez-Prior, \u00c1., and Berm\u00fadez-Oria, A. (2021). Nephroprotective effect of the virgin olive oil polyphenol hydroxytyrosol in type 1-like experimental diabetes mellitus: Relationships with its antioxidant effect. Antioxidants, 10.","DOI":"10.3390\/antiox10111783"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Costantini, F., Di Sano, C., and Barbieri, G. (2020). The hydroxytyrosol induces the death for apoptosis of human melanoma cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218074"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Goldsmith, C.D., Bond, D.R., Jankowski, H., Weidenhofer, J., Stathopoulos, C.E., Roach, P.D., and Scarlett, C. (2018). The olive biophenols oleuropein and hydroxytyrosol selectively reduce proliferation, influence the cell cycle, and induce apoptosis in pancreatic cancer cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19071937"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"373","DOI":"10.3389\/fncel.2018.00373","article-title":"Phenolic compounds characteristic of the mediterranean diet in mitigating microglia-mediated neuroinflammation","volume":"12","author":"Cerezo","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"112752","DOI":"10.1016\/j.fct.2021.112752","article-title":"Protective effect of olive leaves phenolic compounds against neurodegenerative disorders: Promising alternative for Alzheimer and Parkinson diseases modulation","volume":"159","author":"Hadrich","year":"2022","journal-title":"Food Chem. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1080\/1028415X.2020.1829344","article-title":"Hydroxytyrosol improves mitochondrial energetics of a cellular model of Alzheimer\u2019s disease","volume":"25","author":"Visioli","year":"2022","journal-title":"Nutr. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Romero-M\u00e1rquez, J.M., Navarro-Hortal, M.D., Jim\u00e9nez-Trigo, V., Mu\u00f1oz-Ollero, P., Forbes-Hern\u00e1ndez, T.Y., and Esteban-Mu\u00f1oz, A. (2022). An Olive-Derived Extract 20% Rich in Hydroxytyrosol Prevents \u03b2-Amyloid Aggregation and Oxidative Stress, Two Features of Alzheimer Disease, via SKN-1\/NRF2 and HSP-16.2 in Caenorhabditis elegans. Antioxidants, 11.","DOI":"10.3390\/antiox11040629"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e13084","DOI":"10.1111\/apha.13084","article-title":"Thermoregulatory profile of neurodegeneration-induced dementia of the Alzheimer\u2019s type using intracerebroventricular streptozotocin in rats","volume":"224","author":"Vizin","year":"2018","journal-title":"Acta Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1007\/s00702-018-1928-7","article-title":"Intracerebroventricular streptozotocin induces impaired Barnes maze spatial memory and reduces astrocyte branching in the CA1 and CA3 hippocampal regions","volume":"125","author":"Morel","year":"2018","journal-title":"J. Neural Transm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/nrd3505","article-title":"The amyloid cascade hypothesis for Alzheimer\u2019s disease: An appraisal for the development of therapeutics","volume":"10","author":"Karran","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.14336\/AD.2022.0412","article-title":"Amyloid Cascade Hypothesis for the Treatment of Alzheimer\u2019s Disease: Progress and Challenges","volume":"13","author":"Wu","year":"2022","journal-title":"Aging Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.ejmech.2016.02.049","article-title":"Amyloid cascade in Alzheimer\u2019s disease: Recent advances in medicinal chemistry","volume":"113","author":"Mohamed","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","first-page":"58","article-title":"Barnes maze, a useful task to assess spatial reference memory in the mice","volume":"198","author":"Sunyer","year":"2007","journal-title":"Protoc. Exch."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00210-018-1589-y","article-title":"Assessment of spatial learning and memory in the Barnes maze task in rodents\u2014Methodological consideration","volume":"392","author":"Gawel","year":"2019","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_30","first-page":"139","article-title":"Comparative MR analysis of the entorhinal cortex and hippocampus in diagnosing Alzheimer disease","volume":"20","author":"Juottonen","year":"1999","journal-title":"Am. J. Neuroradiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.febslet.2004.11.083","article-title":"Bilateral injection of isoproterenol into hippocampus induces Alzheimer-like hyperphosphorylation of tau and spatial memory deficit in rat","volume":"579","author":"Sun","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1007\/s10967-018-5928-8","article-title":"Stability assessment of a bovine kidney reference-material candidate","volume":"317","author":"Castro","year":"2018","journal-title":"J. Radioanal. Nucl. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"83001","DOI":"10.1088\/0960-1317\/25\/8\/083001","article-title":"Passive blood plasma separation at the microscale: A review of design principles and microdevices","volume":"25","author":"Tripathi","year":"2015","journal-title":"J. Micromech. Microeng."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1186\/s13195-021-00931-3","article-title":"Serum zinc levels and in vivo beta-amyloid deposition in the human brain","volume":"13","author":"Kim","year":"2021","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"865","DOI":"10.3233\/JAD-140534","article-title":"High manganese, a risk for Alzheimer\u2019s disease: High manganese induces amyloid-\u03b2 related cognitive impairment","volume":"42","author":"Tong","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/iub.1614","article-title":"Dissecting copper homeostasis in diabetes mellitus","volume":"69","author":"Lowe","year":"2017","journal-title":"IUBMB Life"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1093\/jn\/114.1.224","article-title":"Urinary Excretion of Zinc, Copper and Iron in the Streptozotocin-Diabetic Rat12","volume":"114","author":"Lau","year":"1984","journal-title":"J. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1016\/j.bbadis.2016.08.008","article-title":"Modulation of hepatic copper-ATPase activity by insulin and glucagon involves protein kinase A (PKA) signaling pathway","volume":"1862","author":"Cuillel","year":"2016","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Squitti, R., Catalli, C., Gigante, L., Marianetti, M., Rosari, M., Mariani, S., Bucoss, S., Mastromoro, G., Ventriglia, M., and Simonelli, I. (2023). Non-Ceruloplasmin Copper Identifies a Subtype of Alzheimer\u2019s Disease (CuAD): Characterization of the Cognitive Profile and Case of a CuAD Patient Carrying an RGS7 Stop-Loss Variant. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076377"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e12278","DOI":"10.1002\/trc2.12278","article-title":"Olive polyphenols and bioavailable glutathione: Promising results in patients diagnosed with mild Alzheimer\u2019s disease","volume":"8","author":"Marianetti","year":"2022","journal-title":"Alzheimer\u2019s Dement. Transl. Res. Clin. Interv."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Squitti, R., Ventriglia, M., Simonelli, I., Bonvicini, C., Costa, A., and Perini, G. (2021). Copper imbalance in alzheimer\u2019s disease: Meta-analysis of serum, plasma, and brain specimens, and replication study evaluating atp7b gene variants. Biomolecules, 11.","DOI":"10.3390\/biom11070960"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1007\/s12035-015-9132-3","article-title":"Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer\u2019s Disease: In Search of a Relevant Mechanism","volume":"53","author":"Grieb","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1007\/s12640-023-00634-7","article-title":"Challenges and Opportunities of Metal Chelation Therapy in Trace Metals Overload-Induced Alzheimer\u2019s Disease","volume":"41","author":"Chaudhari","year":"2023","journal-title":"Neurotox. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.3390\/ijms16022386","article-title":"Quantitative expression analysis of APP pathway and tau phosphorylation-related genes in the ICV STZ-induced non-human primate model of sporadic Alzheimer\u2019s disease","volume":"16","author":"Park","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s00702-015-1394-4","article-title":"Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer\u2019s disease","volume":"122","author":"Knezovic","year":"2015","journal-title":"J. Neural Transm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2000797","DOI":"10.1002\/mnfr.202000797","article-title":"Hydroxytyrosol Acetate Improves the Cognitive Function of APP\/PS1 Transgenic Mice in ER\u03b2-dependent Manner","volume":"65","author":"Qin","year":"2021","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1002\/mnfr.201600332","article-title":"Hydroxytyrosol mildly improve cognitive function independent of APP processing in APP\/PS1 mice","volume":"60","author":"Peng","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.neulet.2013.10.062","article-title":"Oleuropein aglycone counteracts A\u03b242 toxicity in the rat brain","volume":"558","author":"Luccarini","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1037\/h0077579","article-title":"Memory deficits associated with senescence: A neurophysiological and behavioral study in the rat","volume":"93","author":"Barnes","year":"1979","journal-title":"J. Comp. Physiol. Psychol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e2744","DOI":"10.21769\/BioProtoc.2744","article-title":"Barnes Maze Procedure for Spatial Learning and Memory in Mice","volume":"8","author":"Pitts","year":"2018","journal-title":"Bio. Protoc."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1007\/s12035-019-01729-z","article-title":"Mesenchymal Stem Cells Therapy Improved the Streptozotocin-Induced Behavioral and Hippocampal Impairment in Rats","volume":"57","author":"Pardo","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"236","DOI":"10.5114\/ceji.2015.52837","article-title":"Selected aspects of the action of cobalt ions in the human body","volume":"40","author":"Czarnek","year":"2015","journal-title":"Cent. Eur. J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1159\/000129365","article-title":"Metal concentrations in plasma and cerebrospinal fluid in patients with Alzheimer\u2019s disease","volume":"25","author":"Gerhardsson","year":"2008","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"359S","DOI":"10.3945\/ajcn.111.013458","article-title":"Holotranscobalamin, a marker of vitamin B-12 status: Analytical aspects and clinical utility","volume":"94","author":"Nexo","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1136\/jnnp.74.7.959","article-title":"Low vitamin B-12 status in confirmed Alzheimer\u2019s disease as revealed by serum holotranscobalamin","volume":"74","author":"Refsum","year":"2003","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.1038\/s41380-019-0375-7","article-title":"Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology","volume":"25","author":"Ayton","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1159\/000487685","article-title":"Role of Calcium Sensing Receptor in Streptozotocin-Induced Diabetic Rats Exposed to Renal Ischemia Reperfusion Injury","volume":"43","author":"Hu","year":"2018","journal-title":"Kidney Blood Press. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jnutbio.2004.10.006","article-title":"Activity of olive oil phenols on lymphomonocyte cytosolic calcium","volume":"16","author":"Palmerini","year":"2005","journal-title":"J. Nutr. Biochem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3389\/fnagi.2017.00446","article-title":"Role of copper in the onset of Alzheimer\u2019s disease compared to other metals","volume":"9","author":"Bagheri","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.freeradbiomed.2011.10.446","article-title":"Elevated labile Cu is associated with oxidative pathology in Alzheimer disease","volume":"52","author":"James","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.pneurobio.2011.05.001","article-title":"Iron, zinc and copper in the Alzheimer\u2019s disease brain: A quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion","volume":"94","author":"Schrag","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Yeste, N., Valent, D., Arroyo, L., V\u00e1zquez-G\u00f3mez, M., Garc\u00eda-Contreras, C., and Pumarola, M. (2021). Polyphenols and iugr pregnancies: Effects of the antioxidant hydroxytyrosol on brain neurochemistry and development in a porcine model. Antioxidants, 10.","DOI":"10.3390\/antiox10060884"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5478","DOI":"10.1039\/D1FO00210D","article-title":"Hydroxytyrosol alleviates oxidative stress and neuroinflammation and enhances hippocampal neurotrophic signaling to improve stress-induced depressive behaviors in mice","volume":"12","author":"Zhao","year":"2021","journal-title":"Food Funct."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1148\/radiol.2020192541","article-title":"Cross-sectional and longitudinal assessment of brain iron level in Alzheimer disease using 3-T MRI","volume":"296","author":"Damulina","year":"2020","journal-title":"Radiology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3233\/JAD-130209","article-title":"Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer\u2019s disease detected in vivo with magnetic resonance imaging","volume":"37","author":"Raven","year":"2013","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s10534-018-0134-2","article-title":"Iron metabolism in diabetes-induced Alzheimer\u2019s disease: A focus on insulin resistance in the brain","volume":"31","author":"Chung","year":"2018","journal-title":"BioMetals"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Pal, A., Cerchiaro, G., Rani, I., Ventriglia, M., Rongioletti, M., and Longobardi, A. (2022). Iron in Alzheimer\u2019s Disease: From Physiology to Disease Disabilities. Biomolecules, 12.","DOI":"10.3390\/biom12091248"},{"key":"ref_68","first-page":"439","article-title":"The rat brain in stereotaxic coordinates (2nd edn)","volume":"10","author":"Paxinos","year":"1997","journal-title":"Trends Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"42027","DOI":"10.1038\/srep42027","article-title":"Protective effect of mangiferin on myocardial ischemia-reperfusion injury in streptozotocin-induced diabetic rats: Role of AGE-RAGE\/MAPK pathways","volume":"7","author":"Suchal","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1016\/j.chroma.2008.10.116","article-title":"Measurement of free hydroxytyrosol in microdialysates from blood and brain of anesthetized rats by liquid chromatography with fluorescence detection","volume":"1216","author":"Wu","year":"2009","journal-title":"J. Chromatogr. A"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"109391","DOI":"10.1016\/j.yebeh.2023.109391","article-title":"Refinement of the Barnes and Morris water maze protocols improves characterization of spatial cognitive deficits in the lithium-pilocarpine rat model of epilepsy","volume":"147","author":"Dyomina","year":"2023","journal-title":"Epilepsy Behav."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14950\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:01:56Z","timestamp":1760130116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14950"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,6]]},"references-count":71,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms241914950"],"URL":"https:\/\/doi.org\/10.3390\/ijms241914950","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,6]]}}}