{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T03:03:40Z","timestamp":1777518220645,"version":"3.51.4"},"reference-count":124,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,18]],"date-time":"2023-03-18T00:00:00Z","timestamp":1679097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Kansas Alzheimer\u2019s Disease Research Center (KU ADRC)","award":["P30 AG035982"],"award-info":[{"award-number":["P30 AG035982"]}]},{"name":"University of Kansas Alzheimer\u2019s Disease Research Center (KU ADRC)","award":["NIH U54 HD 090216"],"award-info":[{"award-number":["NIH U54 HD 090216"]}]},{"name":"KU School of Medicine Publication Assistance Fund","award":["P30 AG035982"],"award-info":[{"award-number":["P30 AG035982"]}]},{"name":"KU School of Medicine Publication Assistance Fund","award":["NIH U54 HD 090216"],"award-info":[{"award-number":["NIH U54 HD 090216"]}]},{"name":"Kansas Intellectual and Developmental Disabilities Research Center","award":["P30 AG035982"],"award-info":[{"award-number":["P30 AG035982"]}]},{"name":"Kansas Intellectual and Developmental Disabilities Research Center","award":["NIH U54 HD 090216"],"award-info":[{"award-number":["NIH U54 HD 090216"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>The involvement of iron in the pathogenesis of Alzheimer\u2019s disease (AD) may be multifaceted. Besides potentially inducing oxidative damage, the bioavailability of iron may be limited within the central nervous system, creating a functionally iron-deficient state. By comparing staining results from baseline and modified iron histochemical protocols, iron was found to be more tightly bound within cortical sections from patients with high levels of AD pathology compared to subjects with a diagnosis of something other than AD. To begin examining whether the bound iron could cause a functional iron deficiency, a protein-coding gene expression dataset of initial, middle, and advanced stages of AD from olfactory bulb tissue was analyzed for iron-related processes with an emphasis on anemia-related changes in initial AD to capture early pathogenic events. Indeed, anemia-related processes had statistically significant alterations, and the significance of these changes exceeded those for AD-related processes. Other changes in patients with initial AD included the expressions of transcripts with iron-responsive elements and for genes encoding proteins for iron transport and mitochondrial-related processes. In the latter category, there was a decreased expression for the gene encoding pitrilysin metallopeptidase 1 (PITRM1). Other studies have shown that PITRM1 has an altered activity in patients with AD and is associated with pathological changes in this disease. Analysis of a gene expression dataset from PITRM1-deficient or sufficient organoids also revealed statistically significant changes in anemia-like processes. These findings, together with supporting evidence from the literature, raise the possibility that a pathogenic mechanism of AD could be a functional deficiency of iron contributing to neurodegeneration.<\/jats:p>","DOI":"10.3390\/brainsci13030511","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T04:05:23Z","timestamp":1679285123000},"page":"511","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer\u2019s Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration"],"prefix":"10.3390","volume":"13","author":[{"given":"Steven M.","family":"LeVine","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheila","family":"Tsau","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2097-135X","authenticated-orcid":false,"given":"Sumedha","family":"Gunewardena","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/bs.irn.2020.03.022","article-title":"Status and future directions of clinical trials in Alzheimer\u2019s disease","volume":"154","author":"Perry","year":"2020","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41583-021-00533-w","article-title":"The probabilistic model of Alzheimer disease: The amyloid hypothesis revised","volume":"23","author":"Frisoni","year":"2022","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1038\/d41586-018-05719-4","article-title":"The amyloid hypothesis on trial","volume":"559","author":"Makin","year":"2018","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"106549","DOI":"10.1016\/j.cct.2021.106549","article-title":"Current druggable targets for therapeutic control of Alzheimer\u2019s disease","volume":"109","author":"Gupta","year":"2021","journal-title":"Contemp. Clin. Trials"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"329","DOI":"10.4140\/TCP.n.2022.329","article-title":"Aducanumab for Alzheimer\u2019s Disease: Summarized Data From EMERGE, ENGAGE, and PRIME Studies","volume":"37","author":"Yuksel","year":"2022","journal-title":"Sr. Care Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in Early Alzheimer\u2019s Disease","volume":"388","author":"Swanson","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/bs.irn.2020.01.008","article-title":"The mitochondrial hypothesis: Dysfunction, bioenergetic defects, and the metabolic link to Alzheimer\u2019s disease","volume":"154","author":"Swerdlow","year":"2020","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105562","DOI":"10.1016\/j.bioorg.2021.105562","article-title":"The molecular mechanism, targets, and novel molecules in the treatment of Alzheimer\u2019s disease","volume":"119","author":"Verma","year":"2022","journal-title":"Bioorg. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Liu, Y., Ding, R., Xu, Z., Xue, Y., Zhang, D., Zhang, Y., Li, W., and Li, X. (2021). Roles and Mechanisms of the Protein Quality Control System in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010345"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1089\/ars.2020.8134","article-title":"Preventive and Therapeutic Strategies in Alzheimer\u2019s Disease: Focus on Oxidative Stress, Redox Metals, and Ferroptosis","volume":"34","author":"Perry","year":"2021","journal-title":"Antioxid. Redox Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1007\/s11010-021-04334-8","article-title":"Protein degradation-associated mechanisms that are affected in Alzheimer\u2019s disease","volume":"477","year":"2022","journal-title":"Mol. Cell. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"630502","DOI":"10.3389\/fnins.2021.630502","article-title":"APOE and Alzheimer\u2019s Disease: From Lipid Transport to Physiopathology and Therapeutics","volume":"15","author":"Husain","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"35514","DOI":"10.1038\/srep35514","article-title":"Colocalization of cerebral iron with Amyloid beta in Mild Cognitive Impairment","volume":"6","author":"Li","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.nicl.2017.08.019","article-title":"Quantitative susceptibility mapping to evaluate the early stage of Alzheimer\u2019s disease","volume":"16","author":"Kim","year":"2017","journal-title":"NeuroImage: Clin."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1021\/acschemneuro.8b00194","article-title":"Increased Iron Deposition on Brain Quantitative Susceptibility Mapping Correlates with Decreased Cognitive Function in Alzheimer\u2019s Disease","volume":"9","author":"Du","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1093\/brain\/awaa089","article-title":"Relationship between cortical iron and tau aggregation in Alzheimer\u2019s disease","volume":"143","author":"Spotorno","year":"2020","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4248","DOI":"10.1074\/jbc.M110.158980","article-title":"Iron Promotes the Toxicity of Amyloid \u03b2 Peptide by Impeding Its Ordered Aggregation","volume":"286","author":"Liu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"118535","DOI":"10.1016\/j.bbamcr.2019.118535","article-title":"Iron homeostasis and oxidative stress: An intimate relationship","volume":"1866","author":"Galaris","year":"2019","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101494","DOI":"10.1016\/j.redox.2020.101494","article-title":"Iron dyshomeostasis, lipid peroxidation and perturbed expression of cystine\/glutamate antiporter in Alzheimer\u2019s disease: Evidence of ferroptosis","volume":"32","author":"Ashraf","year":"2020","journal-title":"Redox Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1002\/alz.12282","article-title":"Regional brain iron associated with deterioration in Alzheimer\u2019s disease: A large cohort study and theoretical significance","volume":"17","author":"Ayton","year":"2021","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1111\/jnc.15519","article-title":"Ferroptosis as a mechanism of neurodegeneration in Alzheimer\u2019s disease","volume":"159","author":"Jakaria","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/S0006-8993(97)00470-8","article-title":"Iron deposits in multiple sclerosis and Alzheimer\u2019s disease brains","volume":"760","author":"LeVine","year":"1997","journal-title":"Brain Res."},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1046\/j.1471-4159.2000.0740270.x","article-title":"In Situ Oxidative Catalysis by Neurofibrillary Tangles and Senile Plaques in Alzheimer\u2019s Disease: A Central Role for Bound Transition Metals","volume":"74","author":"Sayre","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1007\/s11064-007-9360-7","article-title":"Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease","volume":"32","author":"Castellani","year":"2007","journal-title":"Neurochem. Res."},{"key":"ref_28","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-\u03b2 Peptide","volume":"20","author":"Nair","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9024","DOI":"10.1021\/ic201233b","article-title":"Iron(II) Binding to Amyloid-\u03b2, the Alzheimer\u2019s Peptide","volume":"50","author":"Bijani","year":"2011","journal-title":"Inorg. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1039\/c8mt00146d","article-title":"The human iron-proteome\u2020","volume":"10","author":"Andreini","year":"2018","journal-title":"Metallomics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jalz.2011.10.007","article-title":"National Institute on Aging\u2013Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease","volume":"8","author":"Hyman","year":"2012","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1759091420982169","DOI":"10.1177\/1759091420982169","article-title":"A Simplified Method for the Histochemical Detection of Iron in Paraffin Sections: Intracellular Iron Deposits in Central Nervous System Tissue","volume":"13","author":"LeVine","year":"2021","journal-title":"ASN Neuro"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"69663","DOI":"10.18632\/oncotarget.18193","article-title":"Progressive modulation of the human olfactory bulb transcriptome during Alzheimer\u2019s disease evolution: Novel insights into the olfactory signaling across proteinopathies","volume":"8","author":"Zelaya","year":"2017","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/biostatistics\/4.2.249","article-title":"Exploration, normalization, and summaries of high density oligonucleotide array probe level data","volume":"4","author":"Irizarry","year":"2003","journal-title":"Biostatistics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Methodol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5733","DOI":"10.1038\/s41380-020-0807-4","article-title":"Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer\u2019s disease-like pathology in human cerebral organoids","volume":"26","author":"Ivanyuk","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.3233\/JAD-210200","article-title":"Iron Responsive Element-Mediated Responses to Iron Dyshomeostasis in Alzheimer\u2019s Disease","volume":"84","author":"Hin","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"The UniProt Consortium (2021). UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res., 49, D480\u2013D489.","DOI":"10.1093\/nar\/gkaa1100"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41582-018-0097-5","article-title":"Olfactory and other sensory impairments in Alzheimer disease","volume":"15","author":"Murphy","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1097\/00001756-200102120-00021","article-title":"Olfactory centres in Alzheimer\u2019s disease: Olfactory bulb is involved in early Braak\u2019s stages","volume":"12","author":"Cairns","year":"2001","journal-title":"Neuroreport"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Jobin, B., Boller, B., and Frasnelli, J. (2021). Volumetry of Olfactory Structures in Mild Cognitive Impairment and Alzheimer\u2019s Disease: A Systematic Review and a Meta-Analysis. Brain Sci., 11.","DOI":"10.3390\/brainsci11081010"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"a018945","DOI":"10.1101\/cshperspect.a018945","article-title":"Adult Olfactory Bulb Neurogenesis","volume":"8","author":"Lledo","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_44","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_45","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1038\/s41418-020-00685-9","article-title":"Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer\u2019s disease","volume":"28","author":"Bao","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0165-0173(01)00056-X","article-title":"Rethinking the role of ceruloplasmin in brain iron metabolism","volume":"35","author":"Qian","year":"2001","journal-title":"Brain Res. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"523","DOI":"10.3233\/JAD-2012-111169","article-title":"Overexpression of Human Wild-Type Amyloid-\u03b2 Protein Precursor Decreases the Iron Content and Increases the Oxidative Stress of Neuroblastoma SH-SY5Y Cells","volume":"30","author":"Wan","year":"2012","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1038\/s41380-020-0762-0","article-title":"Amyloidogenic processing of Alzheimer\u2019s disease \u03b2-amyloid precursor protein induces cellular iron retention","volume":"25","author":"Tsatsanis","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"240","DOI":"10.3892\/or.2021.8191","article-title":"Dihydroartemisinin triggers ferroptosis in primary liver cancer cells by promoting and unfolded protein response-induced upregulation of CHAC1 expression","volume":"46","author":"Wang","year":"2021","journal-title":"Oncol. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ripa, R., Dolfi, L., Terrigno, M., Pandolfini, L., Savino, A., Arcucci, V., Groth, M., Tozzini, E.T., Baumgart, M., and Cellerino, A. (2017). MicroRNA miR-29 controls a compensatory response to limit neuronal iron accumulation during adult life and aging. BMC Biol., 15.","DOI":"10.1186\/s12915-017-0354-x"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"eabg4302","DOI":"10.1126\/sciadv.abg4302","article-title":"Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5","volume":"7","author":"Terzi","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"661317","DOI":"10.3389\/fcell.2021.661317","article-title":"Exosomes From miR-19b-3p-Modified ADSCs Inhibit Ferroptosis in Intracerebral Hemorrhage Mice","volume":"9","author":"Yi","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.cmet.2013.02.004","article-title":"Iron and Copper in Mitochondrial Diseases","volume":"17","author":"Xu","year":"2013","journal-title":"Cell Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.neuro.2021.11.003","article-title":"Mitochondrial iron metabolism and neurodegenerative diseases","volume":"88","author":"Cheng","year":"2022","journal-title":"Neurotoxicology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4152","DOI":"10.1073\/pnas.1119338109","article-title":"Disruption of ATP-binding cassette B8 in mice leads to cardiomyopathy through a decrease in mitochondrial iron export","volume":"109","author":"Ichikawa","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"108661","DOI":"10.1016\/j.abb.2020.108661","article-title":"Evolution of the human mitochondrial ABCB7 [2Fe\u20132S](GS)4 cluster exporter and the molecular mechanism of an E433K disease-causing mutation","volume":"697","author":"Pearson","year":"2021","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"mfab015","DOI":"10.1093\/mtomcs\/mfab015","article-title":"Glutathione-coordinated metal complexes as substrates for cellular transporters","volume":"13","author":"Pearson","year":"2021","journal-title":"Metallomics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.1093\/hmg\/ddn244","article-title":"The in vivo mitochondrial two-step maturation of human frataxin","volume":"17","author":"Schmucker","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4166","DOI":"10.1074\/jbc.M308143200","article-title":"Respiration-dependent Removal of Exogenous H2O2 in Brain Mitochondria: Inhibition by Ca2+","volume":"279","author":"Zoccarato","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1016\/j.freeradbiomed.2009.02.025","article-title":"Glutathione S-transferase \u03c0 localizes in mitochondria and protects against oxidative stress","volume":"46","author":"Goto","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3233\/JAD-2011-101716","article-title":"Decreased Proteolytic Activity of the Mitochondrial Amyloid-\u03b2 Degrading Enzyme, PreP Peptidasome, in Alzheimer\u2019s Disease Brain Mitochondria","volume":"27","author":"Alikhani","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.neurobiolaging.2014.09.027","article-title":"Alzheimer\u2019s disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes","volume":"36","author":"Sekar","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/j.bbabio.2014.02.007","article-title":"Mitochondrial import and degradation of amyloid-\u03b2 peptide","volume":"1837","author":"Pinho","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Brunetti, D., Catania, A., Viscomi, C., Deleidi, M., Bindoff, L., Ghezzi, D., and Zeviani, M. (2021). Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070833"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"176","DOI":"10.15252\/emmm.201505894","article-title":"Defective PITRM 1 mitochondrial peptidase is associated with A\u03b2 amyloidotic neurodegeneration","volume":"8","author":"Brunetti","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/s41591-019-0375-9","article-title":"Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer\u2019s disease","volume":"25","author":"Cafini","year":"2019","journal-title":"Nat. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.electacta.2017.03.175","article-title":"Electrochemical studies of tau protein-iron interactions\u2014Potential implications for Alzheimer\u2019s Disease","volume":"236","author":"Ahmadi","year":"2017","journal-title":"Electrochim. Acta"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"110987","DOI":"10.1016\/j.jinorgbio.2019.110987","article-title":"Exploring the interactions of iron and zinc with the microtubule binding repeats R1 and R4","volume":"205","author":"Ahmadi","year":"2020","journal-title":"J. Inorg. Biochem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"276","DOI":"10.3389\/fnmol.2018.00276","article-title":"Untangling Tau and Iron: Exploring the Interaction Between Iron and Tau in Neurodegeneration","volume":"11","author":"Rao","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"525","DOI":"10.3233\/ADR-200234","article-title":"Correlative Microscopy to Localize and Characterize Iron Deposition in Alzheimer\u2019s Disease","volume":"4","author":"Madsen","year":"2020","journal-title":"J. Alzheimer\u2019s Dis. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1046\/j.1471-4159.2002.t01-1-01061.x","article-title":"Iron (III) induces aggregation of hyperphosphorylated \u03c4 and its reduction to iron (II) reverses the aggregation: Implications in the formation of neurofibrillary tangles of Alzheimer\u2019s disease","volume":"82","author":"Yamamoto","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_72","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_73","doi-asserted-by":"crossref","first-page":"1759091416670978","DOI":"10.1177\/1759091416670978","article-title":"Enhanced Histochemical Detection of Iron in Paraffin Sections of Mouse Central Nervous System Tissue: Application in the APP\/PS1 Mouse Model of Alzheimer\u2019s Disease","volume":"8","author":"Sands","year":"2016","journal-title":"ASN Neuro"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3233\/JAD-2010-101503","article-title":"Effect of Cerebral Amyloid Angiopathy on Brain Iron, Copper, and Zinc in Alzheimer\u2019s Disease","volume":"24","author":"Schrag","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1161\/STROKEAHA.118.021872","article-title":"Cerebral Amyloid Angiopathy with Vascular Iron Accumulation and Calcification","volume":"49","author":"Bulk","year":"2018","journal-title":"Stroke"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.arr.2004.02.002","article-title":"Heme, iron, and the mitochondrial decay of ageing","volume":"3","author":"Atamna","year":"2004","journal-title":"Ageing Res. Rev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"255","DOI":"10.3233\/JAD-2006-102-310","article-title":"Heme binding to Amyloid-\u03b2 peptide: Mechanistic role in Alzheimer\u2019s disease","volume":"10","author":"Atamna","year":"2006","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1073\/pnas.0600134103","article-title":"Amyloid-\u03b2 peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer\u2019s disease","volume":"103","author":"Atamna","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1111\/jnc.13425","article-title":"Iron neurochemistry in Alzheimer\u2019s disease and Parkinson\u2019s disease: Targets for therapeutics","volume":"139 Suppl 1","author":"Belaidi","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5276","DOI":"10.1182\/blood-2011-10-388132","article-title":"Heme-regulated eIF2\u03b1 kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis","volume":"119","author":"Suragani","year":"2012","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e62048","DOI":"10.7554\/eLife.62048","article-title":"Small molecule cognitive enhancer reverses age-related memory decline in mice","volume":"9","author":"Krukowski","year":"2020","journal-title":"eLife"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.peptides.2005.09.002","article-title":"Copper binding properties of a tau peptide associated with Alzheimer\u2019s disease studied by CD, NMR, and MALDI-TOF MS","volume":"27","author":"Ma","year":"2006","journal-title":"Peptides"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jelechem.2012.05.023","article-title":"Label-free electrochemical detection of Amyloid beta aggregation in the presence of iron, copper and zinc","volume":"681","author":"Hung","year":"2012","journal-title":"J. Electroanal. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1097\/00002093-199100510-00004","article-title":"Hypothesis Regarding Amyloid and Zinc in the Pathogenesis of Alzheimer Disease: Potential for Preventive Intervention","volume":"5","author":"Constantinidis","year":"1991","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.mehy.2007.04.051","article-title":"Alzheimer\u2019s disease as copper deficiency","volume":"70","author":"Klevay","year":"2008","journal-title":"Med. Hypotheses"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.bbapap.2015.04.030","article-title":"Discovery of compounds that protect tyrosine hydroxylase activity through different mechanisms","volume":"1854","author":"Hole","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1007\/s00775-019-01731-9","article-title":"Redox active metals in neurodegenerative diseases","volume":"24","author":"Acevedo","year":"2019","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"S952","DOI":"10.1093\/ajcn\/67.5.952S","article-title":"Essentiality of copper in humans","volume":"67","author":"Uauy","year":"1998","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/jnr.23143","article-title":"Copper signaling in the mammalian nervous system: Synaptic effects","volume":"91","author":"Gaier","year":"2013","journal-title":"J. Neurosci. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1469-8137.2008.02747.x","article-title":"Iron availability affects the function of mitochondria in cucumber roots","volume":"182","author":"Vigani","year":"2009","journal-title":"New Phytol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"616920","DOI":"10.3389\/fcvm.2020.616920","article-title":"Iron-Deficiency Anemia Results in Transcriptional and Metabolic Remodeling in the Heart Toward a Glycolytic Phenotype","volume":"7","author":"Chung","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1097\/00005072-199311000-00004","article-title":"Functional alterations in Alzheimer\u2019s disease: Diminution of cytochrome oxidase in the hippocampal formation","volume":"52","author":"Simonian","year":"1993","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1046\/j.1471-4159.1994.63062179.x","article-title":"Cortical Cytochrome Oxidase Activity Is Reduced in Alzheimer\u2019s Disease","volume":"63","author":"Mutisya","year":"1994","journal-title":"J. Neurochem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1016\/S0042-6989(96)00210-6","article-title":"Cytochrome oxidase in Alzheimer\u2019s disease: Biochemical, histochemical, and immunohistochemical analyses of the visual and other systems","volume":"37","author":"Antuono","year":"1997","journal-title":"Vis. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/S0197-4580(00)00112-3","article-title":"A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients","volume":"21","author":"Maurer","year":"2000","journal-title":"Neurobiol. Aging"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/jnr.10389","article-title":"Role of mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"70","author":"Castellani","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1017\/neu.2020.43","article-title":"Systematic review and meta-analysis on the role of mitochondrial cytochrome c oxidase in Alzheimer\u2019s disease","volume":"33","author":"Morais","year":"2021","journal-title":"Acta Neuropsychiatr."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s10863-006-9052-z","article-title":"Cytochrome c oxidase subunit IV is essential for assembly and respiratory function of the enzyme complex","volume":"38","author":"Li","year":"2006","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"6440","DOI":"10.2174\/1381612811319360005","article-title":"Key Role of Mitochondria in Alzheimer\u2019s Disease Synaptic Dysfunction","volume":"19","author":"Cavallucci","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1126\/science.272.5265.1136","article-title":"The Whole Structure of the 13-Subunit Oxidized Cytochrome c Oxidase at 2.8 \u00c5","volume":"272","author":"Tsukihara","year":"1996","journal-title":"Science"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1038\/s41422-018-0071-1","article-title":"Structure of the intact 14-subunit human cytochrome c oxidase","volume":"28","author":"Zong","year":"2018","journal-title":"Cell Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.mito.2020.10.004","article-title":"Complex IV\u2014The regulatory center of mitochondrial oxidative phosphorylation","volume":"58","author":"Kadenbach","year":"2021","journal-title":"Mitochondrion"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"345","DOI":"10.2217\/nmt.15.19","article-title":"Targeting mitochondrial metal dyshomeostasis for the treatment of neurodegeneration","volume":"5","author":"Liddell","year":"2015","journal-title":"Neurodegener. Dis. Manag."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1023\/A:1009274131473","article-title":"Decrease of cytochrome c oxidase protein in heart mitochondria of copper-deficient rats","volume":"11","author":"Rossi","year":"1998","journal-title":"Biometals"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1203\/00006450-200008000-00009","article-title":"Perinatal Iron Deficiency Decreases Cytochrome c Oxidase (CytOx) Activity in Selected Regions of Neonatal Rat Brain","volume":"48","author":"Rao","year":"2000","journal-title":"Pediatr. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"711227","DOI":"10.3389\/fmolb.2021.711227","article-title":"Role of Copper on Mitochondrial Function and Metabolism","volume":"8","author":"Ruiz","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1212\/WNL.44.6.1090","article-title":"Electron transport chain defects in Alzheimer\u2019s disease brain","volume":"44","author":"Parker","year":"1994","journal-title":"Neurology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1212\/WNL.45.3.482","article-title":"Cytochrome C Oxidase in Alzheimer\u2019s Disease Brain: Purification and Characterization","volume":"45","author":"Parker","year":"1995","journal-title":"Neurology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"11153","DOI":"10.1073\/pnas.0404349101","article-title":"A role for heme in Alzheimer\u2019s disease: Heme binds amyloid and has altered metabolism","volume":"101","author":"Atamna","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.neulet.2009.06.007","article-title":"Heme-a, the heme prosthetic group of cytochrome c oxidase, is increased in Alzheimer\u2019s disease","volume":"461","author":"Dwyer","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1007\/s00702-009-0324-8","article-title":"Analysis of the genes coding for subunit 10 and 15 of cytochrome c oxidase in Alzheimer\u2019s disease","volume":"116","author":"Vitali","year":"2009","journal-title":"J. Neural Transm."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"5066","DOI":"10.1093\/hmg\/dds350","article-title":"A defect in the mitochondrial complex III, but not complex IV, triggers early ROS-dependent damage in defined brain regions","volume":"21","author":"Diaz","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"14163","DOI":"10.1073\/pnas.0705738104","article-title":"Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer\u2019s disease","volume":"104","author":"Fukui","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.mito.2007.06.001","article-title":"Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer\u2019s disease","volume":"7","author":"Atamna","year":"2007","journal-title":"Mitochondrion"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.tins.2021.06.007","article-title":"Cellular senescence at the crossroads of inflammation and Alzheimer\u2019s disease","volume":"44","author":"Guerrero","year":"2021","journal-title":"Trends Neurosci."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s12035-020-02109-8","article-title":"DNA Double-Strand Break Accumulation in Alzheimer\u2019s Disease: Evidence from Experimental Models and Postmortem Human Brains","volume":"58","author":"Thadathil","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/nrd.2018.109","article-title":"Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing","volume":"17","author":"Boland","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41583-020-0325-z","article-title":"Cellular senescence and Alzheimer disease: The egg and the chicken scenario","volume":"21","author":"Masliah","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Liu, R.-M. (2022). Aging, Cellular Senescence, and Alzheimer\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23041989"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.redox.2017.08.015","article-title":"Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis","volume":"14","author":"Masaldan","year":"2018","journal-title":"Redox Biol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neures.2013.07.005","article-title":"Mitochondrial ferritin in neurodegenerative diseases","volume":"77","author":"Yang","year":"2013","journal-title":"Neurosci. Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.4103\/1673-5374.324847","article-title":"Iron, the endolysosomal system and neuroinflammation: A matter of balance","volume":"17","author":"Borquez","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1182\/blood-2007-07-102335","article-title":"Redistribution of accumulated cell iron: A modality of chelation with therapeutic implications","volume":"111","author":"Sohn","year":"2008","journal-title":"Blood"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1139\/Y09-128","article-title":"Iron redistribution as a therapeutic strategy for treating diseases of localized iron accumulation","volume":"88","author":"Kakhlon","year":"2010","journal-title":"Can. J. Physiol. Pharmacol."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/13\/3\/511\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:58:26Z","timestamp":1760122706000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/13\/3\/511"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,18]]},"references-count":124,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["brainsci13030511"],"URL":"https:\/\/doi.org\/10.3390\/brainsci13030511","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,18]]}}}