{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:38:05Z","timestamp":1789133885060,"version":"build-2803163510"},"reference-count":96,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T00:00:00Z","timestamp":1681344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UTS international scholarship","award":["GNT1105930"],"award-info":[{"award-number":["GNT1105930"]}]},{"name":"NHMRC-ARC Dementia Fellowship","award":["GNT1105930"],"award-info":[{"award-number":["GNT1105930"]}]},{"name":"Mason Foundation","award":["GNT1105930"],"award-info":[{"award-number":["GNT1105930"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>A mis-metabolism of transition metals (i.e., copper, iron, and zinc) in the brain has been recognised as a precursor event for aggregation of Amyloid-\u03b2 plaques, a pathological hallmark of Alzheimer\u2019s disease (AD). However, imaging cerebral transition metals in vivo can be extremely challenging. As the retina is a known accessible extension of the central nervous system, we examined whether changes in the hippocampus and cortex metal load are also mirrored in the retina. Laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to visualise and quantify the anatomical distribution and load of Cu, Fe, and Zn in the hippocampus, cortex, and retina of 9-month-old Amyloid Precursor Protein\/Presenilin 1 (APP\/PS1, n = 10) and Wild Type (WT, n = 10) mice. Our results show a similar metal load trend between the retina and the brain, with the WT mice displaying significantly higher concentrations of Cu, Fe, and Zn in the hippocampus (p &lt; 0.05, p &lt; 0.0001, p &lt; 0.01), cortex (p &lt; 0.05, p = 0.18, p &lt; 0.0001) and the retina (p &lt; 0.001, p = 0.01, p &lt; 0.01) compared with the APP\/PS1 mice. Our findings demonstrate that dysfunction of the cerebral transition metals in AD is also extended to the retina. This could lay the groundwork for future studies on the assessment of transition metal load in the retina in the context of early AD.<\/jats:p>","DOI":"10.3390\/cells12081144","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T01:35:00Z","timestamp":1681349700000},"page":"1144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Distribution of Copper, Iron, and Zinc in the Retina, Hippocampus, and Cortex of the Transgenic APP\/PS1 Mouse Model of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8107-8218","authenticated-orcid":false,"given":"Seyed Mostafa","family":"Hosseinpour Mashkani","sequence":"first","affiliation":[{"name":"Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, 15 Broadway, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P.","family":"Bishop","sequence":"additional","affiliation":[{"name":"Hyphenated Mass Spectrometry Laboratory (HyMaS), School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, 15 Broadway, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Newsha","family":"Raoufi-Rad","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, 15 Broadway, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Adlard","sequence":"additional","affiliation":[{"name":"Synaptic Neurobiology Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8822-1024","authenticated-orcid":false,"given":"Olga","family":"Shimoni","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, 15 Broadway, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4479-3917","authenticated-orcid":false,"given":"S. Mojtaba","family":"Golzan","sequence":"additional","affiliation":[{"name":"Vision Science Group, Graduate School of Health (GSH), University of Technology Sydney, 15 Broadway, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.neulet.2016.04.059","article-title":"Amyloid \u03b2 accumulation and inner retinal degenerative changes in Alzheimer\u2019s disease transgenic mouse","volume":"623","author":"Gupta","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_2","first-page":"309","article-title":"Role of free radicals and metal ions in the pathogenesis of Alzheimer\u2019s disease","volume":"36","author":"Atwood","year":"1999","journal-title":"Met. Ions Biol. Syst."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.ab.2013.07.015","article-title":"Probing copper\/tau protein interactions electrochemically","volume":"442","author":"Martic","year":"2013","journal-title":"Anal. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3751","DOI":"10.1074\/jbc.M116.754101","article-title":"Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by \u03b3-Secretase and Amyloid-\u03b2 Peptide Production","volume":"292","author":"Gerber","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Craddock, T.J., Tuszynski, J.A., Chopra, D., Casey, N., Goldstein, L.E., Hameroff, S.R., and Tanzi, R.E. (2012). The zinc dyshomeostasis hypothesis of Alzheimer\u2019s disease. PLoS ONE, 7.","DOI":"10.1371\/annotation\/57c710a6-83ba-444c-a352-b9f60125f2fa"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/BF03033884","article-title":"Alterations in zinc transporter protein-1 (ZnT-1) in the brain of subjects with mild cognitive impairment, early, and late-stage Alzheimer\u2019s disease","volume":"7","author":"Lovell","year":"2005","journal-title":"Neurotox. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1093\/toxsci\/kfw081","article-title":"Copper Exposure Perturbs Brain Inflammatory Responses and Impairs Clearance of Amyloid-Beta","volume":"152","author":"Kitazawa","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1002\/glia.20416","article-title":"Cellular iron status influences the functional relationship between microglia and oligodendrocytes","volume":"54","author":"Zhang","year":"2006","journal-title":"Glia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1021\/acs.accounts.9b00248","article-title":"Metal Ions in Alzheimer\u2019s Disease: A Key Role or Not?","volume":"52","author":"Liu","year":"2019","journal-title":"Acc. Chem. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s12011-008-8219-3","article-title":"Copper intoxication; antioxidant defenses and oxidative damage in rat brain","volume":"127","author":"Ozcelik","year":"2009","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6727","DOI":"10.1039\/C4CS00138A","article-title":"Biological metals and metal-targeting compounds in major neurodegenerative diseases","volume":"43","author":"Barnham","year":"2014","journal-title":"Chem. Soc. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0022-510X(98)00092-6","article-title":"Copper, iron and zinc in Alzheimer\u2019s disease senile plaques","volume":"158","author":"Lovell","year":"1998","journal-title":"J. Neurol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0891-5849(00)00494-9","article-title":"Redox-active iron mediates amyloid-beta toxicity","volume":"30","author":"Rottkamp","year":"2001","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1006\/bbrc.1995.2678","article-title":"The role of iron in beta amyloid toxicity","volume":"216","author":"Schubert","year":"1995","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1111\/j.1532-5415.1992.tb02014.x","article-title":"A clinicopathological study of CT scans in Alzheimer\u2019s disease","volume":"40","author":"Mendez","year":"1992","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1038\/s41467-018-04529-6","article-title":"Blood-brain barrier opening in Alzheimer\u2019s disease using MR-guided focused ultrasound","volume":"9","author":"Lipsman","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"110017","DOI":"10.1016\/j.ejrad.2021.110017","article-title":"Integrated Positron Emission Tomography\/Magnetic Resonance Imaging in clinical diagnosis of Alzheimer\u2019s disease","volume":"145","author":"Gao","year":"2021","journal-title":"Eur. J. Radiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1097\/NEN.0b013e31824b211b","article-title":"Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005\u20132010","volume":"71","author":"Beach","year":"2012","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1097\/APO.0000000000000505","article-title":"Retinal Biomarkers for Alzheimer Disease: The Facts and the Future","volume":"11","author":"Yuan","year":"2022","journal-title":"Asia-Pac. J. Ophthalmol."},{"key":"ref_20","first-page":"118","article-title":"Advances in instrumental methods for the measurement and speciation of trace metals","volume":"29","author":"Savory","year":"1999","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5383","DOI":"10.1039\/C5SC02231B","article-title":"Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging","volume":"6","author":"Paul","year":"2015","journal-title":"Chem. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jasms.2009.09.022","article-title":"Cerebral Bioimaging of Cu, Fe, Zn, and Mn in the MPTP Mouse Model of Parkinson\u2019s Disease Using Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS)","volume":"21","author":"Matusch","year":"2010","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Linert, W., and Kozlowski, H. (2012). Metal Ions in Neurological Systems, Springer.","DOI":"10.1007\/978-3-7091-1001-0"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1039\/C7MT00349H","article-title":"Multimodal LA-ICP-MS and nanoSIMS imaging enables copper mapping within photoreceptor megamitochondria in a zebrafish model of Menkes disease\u2020","volume":"10","author":"Ackerman","year":"2018","journal-title":"Metallomics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ijms.2006.06.005","article-title":"Imaging of Cu, Zn, Pb and U in human brain tumor resections by laser ablation inductively coupled plasma mass spectrometry","volume":"257","author":"Zoriy","year":"2006","journal-title":"Int. J. Mass Spectrom."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Portbury, S.D., Hare, D.J., Finkelstein, D.I., and Adlard, P.A. (2017). Trehalose improves traumatic brain injury-induced cognitive impairment. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183683"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"116808","DOI":"10.1016\/j.neuroimage.2020.116808","article-title":"Quantitative MRI and laser ablation-inductively coupled plasma-mass spectrometry imaging of iron in the frontal cortex of healthy controls and Alzheimer\u2019s disease patients","volume":"215","author":"Bulk","year":"2020","journal-title":"NeuroImage"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.talanta.2019.01.056","article-title":"Laser ablation ICP-MS for simultaneous quantitative imaging of iron and ferroportin in hippocampus of human brain tissues with Alzheimer\u2019s disease","volume":"197","author":"Fernandez","year":"2019","journal-title":"Talanta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.neuroimage.2016.05.057","article-title":"Laser ablation-inductively coupled plasma-mass spectrometry imaging of white and gray matter iron distribution in Alzheimer\u2019s disease frontal cortex","volume":"137","author":"Hare","year":"2016","journal-title":"NeuroImage"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrneurol.2012.227","article-title":"The retina as a window to the brain\u2014From eye research to CNS disorders","volume":"9","author":"London","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s40035-019-0170-z","article-title":"A longitudinal assessment of retinal function and structure in the APP\/PS1 transgenic mouse model of Alzheimer\u2019s disease","volume":"8","author":"Georgevsky","year":"2019","journal-title":"Transl. Neurodegener."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Matei, N., Leahy, S., Blair, N.P., Burford, J., Rahimi, M., and Shahidi, M. (2022). Retinal Vascular Physiology Biomarkers in a 5XFAD Mouse Model of Alzheimer\u2019s Disease. Cells, 11.","DOI":"10.3390\/cells11152413"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1039\/c9mt00267g","article-title":"Characterising the spatial and temporal brain metal profile in a mouse model of tauopathy","volume":"12","author":"Rao","year":"2020","journal-title":"Metallomics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2174\/156720510790274491","article-title":"Alzheimer\u2019s disease and retinal neurodegeneration","volume":"7","author":"Guo","year":"2010","journal-title":"Curr. Alzheimer Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Gengler, S., Hamilton, A., and H\u00f6lscher, C. (2010). Synaptic plasticity in the hippocampus of a APP\/PS1 mouse model of Alzheimer\u2019s disease is impaired in old but not young mice. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009764"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6707","DOI":"10.1021\/ac301156f","article-title":"High-resolution elemental bioimaging of Ca, Mn, Fe, Co, Cu, and Zn employing LA-ICP-MS and hydrogen reaction gas","volume":"84","author":"Lear","year":"2012","journal-title":"Anal. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10418","DOI":"10.1021\/acs.analchem.1c02138","article-title":"Pew(2): Open-Source Imaging Software for Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry","volume":"93","author":"Lockwood","year":"2021","journal-title":"Anal. Chem."},{"key":"ref_38","unstructured":"Atlas, A.M.B. (2023, March 09). Allen Mouse Brain Atlas, Available online: https:\/\/mouse.brain-map.org\/."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18056","DOI":"10.1021\/acsami.9b21800","article-title":"Multiplex Protein Imaging with Secondary Ion Mass Spectrometry Using Metal Oxide Nanoparticle-Conjugated Antibodies","volume":"12","author":"Moon","year":"2020","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0165-0270(97)00079-4","article-title":"Increased amount of zinc in the hippocampus and amygdala of Alzheimer\u2019s diseased brains: A proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material","volume":"76","author":"Danscher","year":"1997","journal-title":"J. Neurosci. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jsb.2005.09.004","article-title":"Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with beta-amyloid deposits in Alzheimer\u2019s disease","volume":"155","author":"Miller","year":"2006","journal-title":"J. Struct. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.neulet.2007.02.077","article-title":"Iron, copper, and iron regulatory protein 2 in Alzheimer\u2019s disease and related dementias","volume":"418","author":"Magaki","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/BF02050527","article-title":"Neutron activation analysis techniques for identifying elemental status in Alzheimer\u2019s disease","volume":"113","author":"Ward","year":"1987","journal-title":"J. Radioanal. Nucl. Chem."},{"key":"ref_44","first-page":"339","article-title":"Imbalances of trace elements related to oxidative damage in Alzheimer\u2019s disease brain","volume":"19","author":"Cornett","year":"1998","journal-title":"Neurotoxicology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.neuroimage.2010.11.073","article-title":"Increased brain iron coincides with early plaque formation in a mouse model of Alzheimer\u2019s disease","volume":"55","author":"Leskovjan","year":"2011","journal-title":"Neuroimage"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.pneurobio.2014.01.002","article-title":"Metabolism and functions of copper in brain","volume":"116","author":"Scheiber","year":"2014","journal-title":"Prog. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"An, Y., Li, S., Huang, X., Chen, X., Shan, H., and Zhang, M. (2022). The Role of Copper Homeostasis in Brain Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232213850"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.pharmthera.2005.11.004","article-title":"Zinc and copper: Pharmacological probes and endogenous modulators of neuronal excitability","volume":"111","author":"Mathie","year":"2006","journal-title":"Pharmacol. Ther."},{"key":"ref_49","first-page":"1227","article-title":"Ophthalmoscopic changes in a patient with Wilson\u2019s disease during long-term penicillamine therapy","volume":"10","author":"Dingle","year":"1978","journal-title":"Ann. Ophthalmol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.exer.2008.04.013","article-title":"Copper and zinc distribution in the human retina: Relationship to cadmium accumulation, age, and gender","volume":"87","author":"Wills","year":"2008","journal-title":"Exp. Eye Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"44670","DOI":"10.1074\/jbc.M204379200","article-title":"Overexpression of Alzheimer\u2019s disease amyloid-beta opposes the age-dependent elevations of brain copper and iron","volume":"277","author":"Maynard","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_52","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_53","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1039\/C7MT00074J","article-title":"Evidence for widespread, severe brain copper deficiency in Alzheimer\u2019s dementia","volume":"9","author":"Xu","year":"2017","journal-title":"Metallomics"},{"key":"ref_54","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":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s00249-007-0234-3","article-title":"Copper binding to the Alzheimer\u2019s disease amyloid precursor protein","volume":"37","author":"Kong","year":"2008","journal-title":"Eur. Biophys. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"14187","DOI":"10.1073\/pnas.2332818100","article-title":"Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice","volume":"100","author":"Bayer","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.3233\/JAD-140765","article-title":"Is brain copper deficiency in Alzheimer\u2019s, Lewy body, and Creutzfeldt Jakob diseases the common key for a free radical mechanism and oxidative stress-induced damage?","volume":"43","author":"Deloncle","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.molmed.2007.12.002","article-title":"Amyloid beta, mitochondrial dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer\u2019s disease","volume":"14","author":"Reddy","year":"2008","journal-title":"Trends. Mol. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1159\/000065701","article-title":"Brain iron metabolism and neurodegenerative disorders","volume":"24","author":"Sipe","year":"2002","journal-title":"Dev. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1146\/annurev.nutr.20.1.627","article-title":"Iron regulatory proteins and the molecular control of mammalian iron metabolism","volume":"20","author":"Eisenstein","year":"2000","journal-title":"Annu. Rev. Nutr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1007\/s13311-015-0378-2","article-title":"Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of \u03b2-Amyloid Toxicity and Are Mediated by Tau","volume":"12","author":"Li","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.bbagen.2008.12.001","article-title":"Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases","volume":"1790","author":"Cahill","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1111\/j.1582-4934.2008.00356.x","article-title":"A potential pathogenetic role of iron in Alzheimer\u2019s disease","volume":"12","author":"Silvestri","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1167\/iovs.08-2850","article-title":"Dysfunction of the retinal pigment epithelium with age: Increased iron decreases phagocytosis and lysosomal activity","volume":"50","author":"Chen","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.preteyeres.2007.07.004","article-title":"Iron homeostasis and toxicity in retinal degeneration","volume":"26","author":"He","year":"2007","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1016\/j.ajpath.2014.07.008","article-title":"A high serum iron level causes mouse retinal iron accumulation despite an intact blood-retinal barrier","volume":"184","author":"Zhao","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2174\/156652307779940252","article-title":"Gene therapy for ocular neovascularization","volume":"7","author":"Campochiaro","year":"2007","journal-title":"Curr. Gene Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fnagi.2013.00024","article-title":"Retinal iron homeostasis in health and disease","volume":"5","author":"Song","year":"2013","journal-title":"Front. Aging Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Pamphlett, R., Cherepanoff, S., Too, L.K., Kum Jew, S., Doble, P.A., and Bishop, D.P. (2020). The distribution of toxic metals in the human retina and optic nerve head: Implications for age-related macular degeneration. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0241054"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1097\/WNR.0b013e3280107776","article-title":"Iron levels in human retina: Sex difference and increase with age","volume":"17","author":"Hahn","year":"2006","journal-title":"Neuroreport"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/0014-4835(83)90138-0","article-title":"Elemental concentrations in ocular tissues of various species","volume":"37","author":"Eckhert","year":"1983","journal-title":"Exp. Eye Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/nm.2613","article-title":"Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export","volume":"18","author":"Lei","year":"2012","journal-title":"Nat. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1523\/JNEUROSCI.1907-15.2016","article-title":"In Vivo MRI Mapping of Brain Iron Deposition across the Adult Lifespan","volume":"36","author":"Betts","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"632","DOI":"10.3389\/fnins.2018.00632","article-title":"Iron and Alzheimer\u2019s Disease: From Pathogenesis to Therapeutic Implications","volume":"12","author":"Liu","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/jnr.490310214","article-title":"Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer\u2019s disease","volume":"31","author":"Connor","year":"1992","journal-title":"J. Neurosci. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/2051-5960-1-55","article-title":"The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer\u2019s disease","volume":"1","author":"Raha","year":"2013","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.chembiol.2017.07.014","article-title":"Iron Biochemistry is Correlated with Amyloid Plaque Morphology in an Established Mouse Model of Alzheimer\u2019s Disease","volume":"24","author":"Telling","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Takeda, A., Takada, S., Nakamura, M., Suzuki, M., Tamano, H., Ando, M., and Oku, N. (2011). Transient increase in Zn2+ in hippocampal CA1 pyramidal neurons causes reversible memory deficit. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028615"},{"key":"ref_79","first-page":"144","article-title":"Zinc and its importance for human health: An integrative review","volume":"18","author":"Roohani","year":"2013","journal-title":"J. Res. Med. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s12291-015-0503-3","article-title":"Regional Distribution of Copper, Zinc and Iron in Brain of Wistar Rat Model for Non-Wilsonian Brain Copper Toxicosis","volume":"31","author":"Pal","year":"2016","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0301-0082(00)00057-5","article-title":"Zinc in the retina","volume":"64","author":"Ugarte","year":"2001","journal-title":"Prog. Neurobiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.ajo.2008.08.014","article-title":"Reduced zinc and copper in the retinal pigment epithelium and choroid in age-related macular degeneration","volume":"147","author":"Erie","year":"2009","journal-title":"Am. J. Ophthalmol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1080\/07315724.2001.10719022","article-title":"Zinc and the eye","volume":"20","author":"Grahn","year":"2001","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/nrn1671","article-title":"The neurobiology of zinc in health and disease","volume":"6","author":"Frederickson","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"10784","DOI":"10.1074\/jbc.M707109200","article-title":"Identifying the minimal copper- and zinc-binding site sequence in amyloid-beta peptides","volume":"283","author":"Minicozzi","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3233\/JAD-2010-1346","article-title":"NMR studies of zinc, copper, and iron binding to histidine, the principal metal ion complexing site of amyloid-beta peptide","volume":"20","author":"Nair","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4772","DOI":"10.1038\/s41598-018-23122-x","article-title":"Zinc ion rapidly induces toxic, off-pathway amyloid-\u03b2 oligomers distinct from amyloid-\u03b2 derived diffusible ligands in Alzheimer\u2019s disease","volume":"8","author":"Lee","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1212\/01.wnl.0000223644.08653.b5","article-title":"Elevated cortical zinc in Alzheimer disease","volume":"67","author":"Religa","year":"2006","journal-title":"Neurology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1523\/JNEUROSCI.5255-09.2010","article-title":"Cognitive loss in zinc transporter-3 knock-out mice: A phenocopy for the synaptic and memory deficits of Alzheimer\u2019s disease?","volume":"30","author":"Adlard","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Hancock, S.M., Portbury, S.D., Gunn, A.P., Roberts, B.R., Bush, A.I., and Adlard, P.A. (2020). Zinc Transporter-3 Knockout Mice Demonstrate Age-Dependent Alterations in the Metalloproteome. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030839"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s13041-019-0528-2","article-title":"Zinc transporters in Alzheimer\u2019s disease","volume":"12","author":"Xu","year":"2019","journal-title":"Mol. Brain"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1016\/j.visres.2004.07.038","article-title":"Localization of zinc transporter-3 (ZnT-3) in mouse retina","volume":"44","author":"Redenti","year":"2004","journal-title":"Vision Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s12263-013-0379-x","article-title":"Zinc and the aging brain","volume":"9","author":"Nuttall","year":"2014","journal-title":"Genes Nutr."},{"key":"ref_94","unstructured":"Perez, C.M. (2019). Interplay between Synaptic GPCRs in Alzheimer\u2019s Disease. [Ph.D. Thesis, University of Bristol]."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1111\/j.1476-5381.2011.01299.x","article-title":"Animal models in the drug discovery pipeline for Alzheimer\u2019s disease","volume":"164","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3990","DOI":"10.1021\/ac300374x","article-title":"Three-dimensional atlas of iron, copper, and zinc in the mouse cerebrum and brainstem","volume":"84","author":"Hare","year":"2012","journal-title":"Anal. Chem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/8\/1144\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:15:07Z","timestamp":1760123707000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/8\/1144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,13]]},"references-count":96,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["cells12081144"],"URL":"https:\/\/doi.org\/10.3390\/cells12081144","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,13]]}}}