{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T07:20:45Z","timestamp":1773472845749,"version":"3.50.1"},"reference-count":173,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,24]],"date-time":"2021-04-24T00:00:00Z","timestamp":1619222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a neurodegenerative disorder, affecting millions of people worldwide, a number expected to exponentially increase in the future since no effective treatments are available so far. AD is characterized by severe cognitive dysfunctions associated with neuronal loss and connection disruption, mainly occurring in specific brain areas such as the hippocampus, cerebral cortex, and amygdala, compromising memory, language, reasoning, and social behavior. Proteomics and redox proteomics are powerful techniques used to identify altered proteins and pathways in AD, providing relevant insights on cellular pathways altered in the disease and defining novel targets exploitable for drug development. Here, we review the main results achieved by both -omics techniques, focusing on the changes occurring in AD mitochondria under oxidative stress and upon copper exposure. Relevant information arises by the comparative analysis of these results, evidencing alterations of common mitochondrial proteins, metabolic cycles, and cascades. Our analysis leads to three shared mitochondrial proteins, playing key roles in metabolism, ATP generation, oxidative stress, and apoptosis. Their potential as targets for development of innovative AD treatments is thus suggested. Despite the relevant efforts, no effective drugs against AD have been reported so far; nonetheless, various compounds targeting mitochondria have been proposed and investigated, reporting promising results.<\/jats:p>","DOI":"10.3390\/life11050386","type":"journal-article","created":{"date-parts":[[2021,4,24]],"date-time":"2021-04-24T21:49:20Z","timestamp":1619300960000},"page":"386","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Dynamic Interplay between Copper Toxicity and Mitochondrial Dysfunction in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-5528","authenticated-orcid":false,"given":"Giusy","family":"Tassone","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy\u2013Department of Excellence 2018\u20132020, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arian","family":"Kola","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy\u2013Department of Excellence 2018\u20132020, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Valensin","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy\u2013Department of Excellence 2018\u20132020, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2574-3911","authenticated-orcid":false,"given":"Cecilia","family":"Pozzi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy\u2013Department of Excellence 2018\u20132020, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1126\/science.1132814","article-title":"A Century of Alzheimer\u2019s Disease","volume":"314","author":"Goedert","year":"2006","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: The amyloid cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.1072994","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease: Progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1016\/j.ajpath.2012.03.004","article-title":"Alzheimer\u2019s Disease 2012","volume":"180","author":"Marchesi","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.tins.2008.06.005","article-title":"Neuronal calcium mishandling and the pathogenesis of Alzheimer\u2019s disease","volume":"31","author":"Bezprozvanny","year":"2008","journal-title":"Trends Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2174\/156720509787313899","article-title":"Cholesterol in Alzheimer\u2019s disease: Unresolved questions","volume":"6","author":"Stefani","year":"2009","journal-title":"Curr. Alzheimer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s11064-009-0087-5","article-title":"Fatty Acid Composition of Frontal, Temporal and Parietal Neocortex in the Normal Human Brain and in Alzheimer\u2019s Disease","volume":"35","author":"Fraser","year":"2010","journal-title":"Neurochem. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1471-4159.2009.05867.x","article-title":"The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer\u2019s disease","volume":"109","author":"Wang","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1007\/s40263-019-00658-8","article-title":"Targeting Mitochondria in Alzheimer Disease: Rationale and Perspectives","volume":"33","author":"Lanzillotta","year":"2019","journal-title":"CNS Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.3233\/JAD-170585","article-title":"Mitochondria and Mitochondrial Cascades in Alzheimer\u2019s Disease","volume":"62","author":"Swerdlow","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_11","first-page":"103","article-title":"Mitochondrial Behavior in Axon Degeneration and Regeneration","volume":"13","author":"Wang","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.redox.2017.10.014","article-title":"Oxidative stress and the amyloid beta peptide in Alzheimer\u2019s disease","volume":"14","author":"Cheignon","year":"2018","journal-title":"Redox Boil."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1021\/cr040410w","article-title":"Copper Homeostasis and Neurodegenerative Disorders (Alzheimer\u2019s, Prion, and Parkinson\u2019s Diseases and Amyotrophic Lateral Sclerosis)","volume":"106","author":"Gaggelli","year":"2006","journal-title":"Chem. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1016\/j.ccr.2009.05.011","article-title":"Copper, iron, and zinc ions homeostasis and their role in neurodegenerative disorders (metal uptake, transport, distribution and regulation)","volume":"253","author":"Kozlowski","year":"2009","journal-title":"Coord. Chem. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gromadzka, G., Tarnacka, B., Flaga, A., and Adamczyk, A. (2020). Copper Dyshomeostasis in Neurodegenerative Diseases\u2014Therapeutic Implications. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239259"},{"key":"ref_16","unstructured":"Royer, A., and Sharman, T. (2021). Copper toxicity. StatPearls, StatPearls Publishing."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Patel, R., and Aschner, M. (2021). Commonalities between Copper Neurotoxicity and Alzheimer\u2019s Disease. Toxics, 9.","DOI":"10.3390\/toxics9010004"},{"key":"ref_18","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":"2015","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s11064-014-1374-3","article-title":"Mechanisms of Astrocyte-Mediated Cerebral Edema","volume":"40","author":"Stokum","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3389\/fnagi.2018.00224","article-title":"Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer\u2019s Disease?","volume":"10","author":"Fulop","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_21","first-page":"1","article-title":"Copper signalling: Causes and consequences","volume":"16","author":"Kardos","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jtemb.2012.04.019","article-title":"Copper toxicity in Alzheimer\u2019s disease: Cognitive loss from ingestion of inorganic copper","volume":"26","author":"Brewer","year":"2012","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1016\/j.ccr.2012.03.013","article-title":"Copper, zinc and iron in neurodegenerative diseases (Alzheimer\u2019s, Parkinson\u2019s and prion diseases)","volume":"256","author":"Kozlowski","year":"2012","journal-title":"Coord. Chem. Rev."},{"key":"ref_24","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_25","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_26","doi-asserted-by":"crossref","first-page":"100105","DOI":"10.1074\/jbc.REV120.008207","article-title":"The essential elements of Alzheimer\u2019s disease","volume":"296","author":"Lei","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.2741\/2133","article-title":"Brain mitochondrial dysfunction in aging: Conditions that improve survival, neurological performance and mitochondrial function","volume":"12","author":"Navarro","year":"2007","journal-title":"Front. Biosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"R985","DOI":"10.1152\/ajpregu.00537.2001","article-title":"Behavioral dysfunction, brain oxidative stress, and impaired mitochondrial electron transfer in aging mice","volume":"282","author":"Navarro","year":"2002","journal-title":"Am. J. Physiol. Integr. Comp. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.jinorgbio.2016.10.009","article-title":"Rat liver mitochondrial dysfunction by addition of copper(II) or iron(III) ions","volume":"166","author":"Acosta","year":"2017","journal-title":"J. Inorg. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1039\/C7MT00075H","article-title":"Potentiating role of copper on spatial memory deficit induced by beta amyloid and evaluation of mitochondrial function markers in the hippocampus of rats","volume":"9","author":"Behzadfar","year":"2017","journal-title":"Metallomics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"630","DOI":"10.2174\/1570159X16666180926123722","article-title":"Omics-based Biomarkers for the Early Alzheimer Disease Diagnosis and Reliable Therapeutic Targets Development","volume":"17","author":"Baquero","year":"2019","journal-title":"Curr. Neuropharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1007\/s10545-012-9480-3","article-title":"Mitochondrial proteomics\u2014A tool for the study of metabolic disorders","volume":"35","author":"Gregersen","year":"2012","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.toxlet.2016.10.009","article-title":"Mitochondrial proteomic alterations caused by long-term low-dose copper exposure in mouse cortex","volume":"263","author":"Lin","year":"2016","journal-title":"Toxicol. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1007\/s00204-018-2163-6","article-title":"Proteomic alterations of brain subcellular organelles caused by low-dose copper exposure: Implication for Alzheimer\u2019s disease","volume":"92","author":"Yu","year":"2018","journal-title":"Arch. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1083\/jcb.200608073","article-title":"Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels","volume":"175","author":"Szabadkai","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.mcn.2012.07.011","article-title":"Mitochondria-associated ER membranes in Alzheimer disease","volume":"55","author":"Schon","year":"2013","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Eysert, F., Kinoshita, P.F., Mary, A., Vaillant-Beuchot, L., Checler, F., and Chami, M. (2020). Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249521"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1006\/bbrc.2000.4109","article-title":"Deranged Expression of Molecular Chaperones in Brains of Patients with Alzheimer\u2019s Disease","volume":"280","author":"Yoo","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3233\/JAD-2010-100966","article-title":"Enhanced Expression of the Voltage-Dependent Anion Channel 1 (VDAC1) in Alzheimer\u2019s Disease Transgenic Mice: An Insight into the Pathogenic Effects of Amyloid-\u03b2","volume":"23","author":"Cabodevilla","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"25552","DOI":"10.1074\/jbc.273.40.25552","article-title":"The Chaperone BiP\/GRP78 Binds to Amyloid Precursor Protein and Decreases A\u03b240 and A\u03b242 Secretion","volume":"273","author":"Yang","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4172\/2157-7412.1000128","article-title":"The Molecular Chaperone GRP78\/BiP as a Therapeutic Target for Neurodegenerative Disorders: A Mini Review","volume":"4","author":"Gorbatyuk","year":"2013","journal-title":"J. Genet. Syndr. Gene Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.mito.2020.11.008","article-title":"Exploring the role of mitochondrial proteins as molecular target in Alzheimer\u2019s disease","volume":"56","author":"Chadha","year":"2021","journal-title":"Mitochondrion"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/s41573-020-0072-x","article-title":"Brain energy rescue: An emerging therapeutic concept for neurodegenerative disorders of ageing","volume":"19","author":"Cunnane","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3386","DOI":"10.1111\/febs.15225","article-title":"Amyloid protein aggregates: New clients for mitochondrial energy production in the brain?","volume":"287","author":"Sivanesan","year":"2020","journal-title":"FEBS J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13041-019-0430-y","article-title":"Quantitative profiling brain proteomes revealed mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"12","author":"Adav","year":"2019","journal-title":"Mol. Brain"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"111385","DOI":"10.1016\/j.mad.2020.111385","article-title":"Mitochondria and cellular redox state on the route from ageing to Alzheimer\u2019s disease","volume":"192","author":"Abate","year":"2020","journal-title":"Mech. Ageing Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1016\/j.cell.2017.07.050","article-title":"Architecture of Human Mitochondrial Respiratory Megacomplex I2III2IV2","volume":"170","author":"Guo","year":"2017","journal-title":"Cell"},{"key":"ref_48","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_49","doi-asserted-by":"crossref","first-page":"4354","DOI":"10.1073\/pnas.96.8.4354","article-title":"The NDUFA1 gene product (MWFE protein) is essential for activity of complex I in mammalian mitochondria","volume":"96","author":"Au","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/ana.21036","article-title":"X-linkedNDUFA1gene mutations associated with mitochondrial encephalomyopathy","volume":"61","author":"Ugalde","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.ymgme.2008.12.004","article-title":"A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease","volume":"96","author":"Potluri","year":"2009","journal-title":"Mol. Genet. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1021\/acs.biochem.6b00190","article-title":"Specific Methylation of Asp160 (49 kDa subunit) Located inside the Quinone Binding Cavity of Bovine Mitochondrial Complex I","volume":"55","author":"Murai","year":"2016","journal-title":"Biochemistry"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"18934","DOI":"10.1073\/pnas.1319247110","article-title":"Assembly factors for the membrane arm of human complex I","volume":"110","author":"Andrews","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1016\/j.bbabio.2013.01.009","article-title":"The mechanism of ubihydroquinone oxidation at the Qo-site of the cytochrome bc1 complex","volume":"1827","author":"Crofts","year":"2013","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.fitote.2006.11.006","article-title":"The effects of Liuwei Dihuang decoction on the gene expression in the hippocampus of senescence-accelerated mouse","volume":"78","author":"Cheng","year":"2007","journal-title":"Fitoterapia"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Kadenbach, B. (2020). Complex IV\u2014The regulatory center of mitochondrial oxidative phosphorylation. Mitochondrion.","DOI":"10.1016\/j.mito.2020.10.004"},{"key":"ref_57","unstructured":"Collins, J.F. (2016). Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals, Academic Press."},{"key":"ref_58","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_59","doi-asserted-by":"crossref","first-page":"29602","DOI":"10.1073\/pnas.2017987117","article-title":"Assembly of the peripheral stalk of ATP synthase in human mitochondria","volume":"117","author":"He","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.jalz.2017.01.016","article-title":"Systems biology approach to late-onset Alzheimer\u2019s disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments","volume":"13","author":"Mukherjee","year":"2017","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.3389\/fnins.2020.530219","article-title":"Metabolic Dysregulation Contributes to the Progression of Alzheimer\u2019s Disease","volume":"14","author":"Yan","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"14038","DOI":"10.1038\/s41598-017-14420-x","article-title":"Late-onset Alzheimer\u2019s disease is associated with inherent changes in bioenergetics profiles","volume":"7","author":"Sonntag","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1515\/hsz-2019-0106","article-title":"Comparative studies of Aspergillus fumigatus 2-methylcitrate synthase and human citrate synthase","volume":"400","author":"Schlachter","year":"2019","journal-title":"Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1110\/ps.8.12.2655","article-title":"The mechanism of aconitase: 1.8 \u00c5 resolution crystal structure of the S642A: Citrate complex","volume":"8","author":"Lloyd","year":"2008","journal-title":"Protein Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/(SICI)1097-0134(20000515)39:3<216::AID-PROT40>3.0.CO;2-#","article-title":"Crystal structure of human ubiquitous mitochondrial creatine kinase","volume":"39","author":"Eder","year":"2000","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.bbadis.2005.09.004","article-title":"Mitochondrial creatine kinase in human health and disease","volume":"1762","author":"Schlattner","year":"2006","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1002\/jnr.10060","article-title":"Altered brain phosphocreatine and ATP regulation when mitochondrial creatine kinase is absent","volume":"66","author":"Khait","year":"2001","journal-title":"J. Neurosci. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1534\/genetics.117.300262","article-title":"Cell Biology of the Mitochondrion","volume":"207","author":"Sedensky","year":"2017","journal-title":"Genetics"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","article-title":"Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease","volume":"20","author":"Butterfield","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_70","first-page":"87","article-title":"Manganese Superoxide Dismutase and Oxidative Stress Modulation","volume":"68","author":"Bresciani","year":"2015","journal-title":"Adv. Appl. Microbiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/01616412.2016.1251711","article-title":"Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders","volume":"39","author":"Islam","year":"2017","journal-title":"Neurol. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/bs.pmbts.2016.12.015","article-title":"Mitochondrial-Targeted Catalase","volume":"146","author":"Dai","year":"2017","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1146\/annurev-biochem-061516-045037","article-title":"Oxidative Stress","volume":"86","author":"Sies","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.brainresbull.2016.06.005","article-title":"Oxidative stress, protein modification and Alzheimer disease","volume":"133","author":"Tramutola","year":"2017","journal-title":"Brain Res. Bull."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5839","DOI":"10.1073\/pnas.1804932115","article-title":"Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine","volume":"115","author":"Radi","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/mas.21374","article-title":"Mass spectrometry and redox proteomics: Applications in disease","volume":"33","author":"Butterfield","year":"2013","journal-title":"Mass Spectrom. Rev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1089\/ars.2011.4109","article-title":"Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications","volume":"17","author":"Butterfield","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.arr.2013.12.005","article-title":"Redox proteomics and the dynamic molecular landscape of the aging brain","volume":"13","author":"Perluigi","year":"2014","journal-title":"Ageing Res. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Butterfield, D.A., and Boyd-Kimball, D. (2020). Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease. Antioxidants, 9.","DOI":"10.3390\/antiox9090818"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1002\/pmic.200300435","article-title":"Redox proteomics: Identification of oxidatively modified proteins","volume":"3","author":"Ghezzi","year":"2003","journal-title":"Proteomics"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1586\/14789450.5.2.157","article-title":"Redox proteomics: Understanding oxidative stress in the progression of age-related neurodegenerative disorders","volume":"5","author":"Butterfield","year":"2008","journal-title":"Expert Rev. Proteom."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/0891-5849(94)90169-4","article-title":"Differential susceptibility of plasma proteins to oxidative modification: Examination by western blot immunoassay","volume":"17","author":"Shacter","year":"1994","journal-title":"Free Radic. Biol. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"20313","DOI":"10.1074\/jbc.272.33.20313","article-title":"Protein Oxidation in Aging, Disease, and Oxidative Stress","volume":"272","author":"Berlett","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3109\/03602539808996310","article-title":"Reactive Oxygen-Mediated Protein Oxidation in Aging and Disease","volume":"30","author":"Stadtman","year":"1998","journal-title":"Drug Metab. Rev."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/724904","article-title":"Oxidative Stress and Down Syndrome: A Route toward Alzheimer-Like Dementia","volume":"2012","author":"Perluigi","year":"2011","journal-title":"Curr. Gerontol. Geriatr. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"194","DOI":"10.5483\/BMBRep.2008.41.3.194","article-title":"Nitrosative Protein Tyrosine Modifications: Biochemistry and Functional Signifi-cance","volume":"41","author":"Yeo","year":"2008","journal-title":"BMB Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1046\/j.1471-4159.1997.69031161.x","article-title":"The Lipid Peroxidation Product, 4-Hydroxy-2-trans-Nonenal, Alters the Conformation of Cortical Synaptosomal Membrane Proteins","volume":"69","author":"Subramaniam","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_88","first-page":"123","article-title":"Proteomics Identification of Carbonylated and HNE-Bound Brain Proteins in Alzheimer\u2019s Disease","volume":"566","author":"Sultana","year":"2009","journal-title":"Adv. Struct. Saf. Stud."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3551","DOI":"10.1002\/(SICI)1522-2683(19991201)20:18<3551::AID-ELPS3551>3.0.CO;2-2","article-title":"Probability-Based Protein Identification by Searching Sequence Data-bases Using Mass Spectrometry Data","volume":"20","author":"Perkins","year":"1999","journal-title":"Electrophoresis"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/1044-0305(94)80016-2","article-title":"An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database","volume":"5","author":"Eng","year":"1994","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1074\/mcp.M400129-MCP200","article-title":"Multiplexed Protein Quantitation in Saccharomyces cerevisiae Using Amine-reactive Isobaric Tagging Reagents","volume":"3","author":"Ross","year":"2004","journal-title":"Mol. Cell. Proteom."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1002\/jms.1978","article-title":"Isotope-coded dimethyl tagging for differential quantification of posttranslational protein carbonylation by 4-hydroxy-2-nonenal, an end-product of lipid peroxidation","volume":"46","author":"Rauniyar","year":"2011","journal-title":"J. Mass Spectrom."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Sharma, V.-K., Singh, T.G., and Mehta, V. (2021). Stressed Mitochondria: A Target to Intrude Alzheimer\u2019s Disease. Mitochondrion.","DOI":"10.1016\/j.mito.2021.04.004"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1002\/prca.200800161","article-title":"Redox proteomics identification of 4-hydroxynonenal-modified brain proteins in Alzheimer\u2019s disease: Role of lipid peroxidation in Alzheimer\u2019s disease pathogenesis","volume":"3","author":"Perluigi","year":"2009","journal-title":"Proteom. Clin. Appl."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.brainres.2009.04.009","article-title":"Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD","volume":"1274","author":"Reed","year":"2009","journal-title":"Brain Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.nbd.2005.10.004","article-title":"Identification of nitrated proteins in Alzheimer\u2019s disease brain using a redox proteomics approach","volume":"22","author":"Sultana","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/j.1750-3639.2009.00266.x","article-title":"Mitochondrial ATP-Synthase in the Entorhinal Cortex Is a Target of Oxidative Stress at Stages I\/II of Alzheimer\u2019s Disease Pathology","volume":"20","author":"Terni","year":"2010","journal-title":"Brain Pathol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1016\/j.jprot.2011.06.015","article-title":"Proteomic identification of specifically carbonylated brain proteins in APPNLh\/APPNLh\u00d7PS-1P264L\/PS-1P264L human double mutant knock-in mice model of Alzheimer disease as a function of age","volume":"74","author":"Sultana","year":"2011","journal-title":"J. Proteom."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.phrs.2018.03.010","article-title":"VDAC1, mitochondrial dysfunction, and Alzheimer\u2019s disease","volume":"131","author":"Gupta","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"11","DOI":"10.15698\/cst2017.10.104","article-title":"VDAC1 at the crossroads of cell metabolism, apoptosis and cell stress","volume":"1","author":"Maldonado","year":"2017","journal-title":"Cell Stress"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1074\/jbc.M111.268920","article-title":"Structure-based Analysis of VDAC1 Protein","volume":"287","author":"Geula","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1042\/BJ20112079","article-title":"Structure-based analysis of VDAC1: N-terminus location, translocation, channel gating and association with anti-apoptotic proteins","volume":"444","author":"Geula","year":"2012","journal-title":"Biochem. J."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1242\/jcs.040188","article-title":"The VDAC1 N-terminus is essential both for apoptosis and the protective effect of anti-apoptotic proteins","volume":"122","author":"Arbel","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"6053","DOI":"10.1074\/jbc.M109.082990","article-title":"Voltage-dependent Anion Channel 1-based Peptides Interact with Bcl-2 to Prevent Antiapoptotic Activity","volume":"285","author":"Arbel","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"23152","DOI":"10.1074\/jbc.M112.345918","article-title":"Mediation of the Antiapoptotic Activity of Bcl-xL Protein upon Interaction with VDAC1 Protein","volume":"287","author":"Arbel","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_106","first-page":"4435","article-title":"VDAC1 as a Player in Mitochondria-Mediated Apoptosis and Target for Modulating Apop-tosis","volume":"24","author":"Varda","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"5131","DOI":"10.1093\/hmg\/dds360","article-title":"Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"21","author":"Manczak","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"13482","DOI":"10.1074\/jbc.M708216200","article-title":"Hexokinase-I Protection against Apoptotic Cell Death Is Mediated via Interaction with the Voltage-dependent Anion Channel-1","volume":"283","author":"Zaid","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"30670","DOI":"10.1074\/jbc.M115.691493","article-title":"The Voltage-dependent Anion Channel 1 Mediates Amyloid \u03b2 Toxicity and Represents a Potential Target for Alzheimer Disease Therapy","volume":"290","author":"Smilansky","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.freeradbiomed.2005.08.045","article-title":"Crystal structure of nitrated human manganese superoxide dismutase: Mechanism of inactivation","volume":"40","author":"Quint","year":"2006","journal-title":"Free Radic. Biol. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1179\/1351000213Y.0000000073","article-title":"Aconitase post-translational modification as a key in linkage between Krebs cycle, iron homeostasis, redox signaling, and metabolism of reactive oxygen species","volume":"19","author":"Lushchak","year":"2013","journal-title":"Redox Rep."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.jprot.2015.04.005","article-title":"Redox proteomics identification of specifically carbonylated proteins in the hippocampi of triple transgenic Alzheimer\u2019s disease mice at its earliest pathological stage","volume":"123","author":"Shen","year":"2015","journal-title":"J. Proteom."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.neurobiolaging.2005.07.001","article-title":"Proteomic identification of proteins specifically oxidized in Caenorhabditis elegans expressing human A\u03b2(1\u201342): Implications for Alzheimer\u2019s disease","volume":"27","author":"Poon","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-45282-0","article-title":"Functional Roles of Metabolic Intermediates in Regulating the Human Mitochondrial NAD(P)+-Dependent Malic Enzyme","volume":"9","author":"Hsieh","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_115","first-page":"257","article-title":"Malate dehydrogenases--structure and function","volume":"21","year":"2002","journal-title":"Gen. Physiol. Biophys."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1002\/ana.20474","article-title":"Mitochondrial abnormalities in Alzheimer brain: Mechanistic implications","volume":"57","author":"Bubber","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/s41583-018-0067-3","article-title":"Imaging the evolution and pathophysiology of Alzheimer disease","volume":"19","author":"Jagust","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jalz.2018.08.005","article-title":"Understanding disease progression and improving Alzheimer\u2019s disease clinical trials: Recent highlights from the Alzheimer\u2019s Disease Neuroimaging Initiative","volume":"15","author":"Veitch","year":"2019","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1093\/geronj\/35.1.45","article-title":"Aspects of Free Radical Reactions in Biological Systems: Aging","volume":"35","author":"Leibovitz","year":"1980","journal-title":"J. Gerontol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.freeradbiomed.2013.05.027","article-title":"SOD2 in mitochondrial dysfunction and neurodegeneration","volume":"62","author":"Flynn","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_121","first-page":"BR8","article-title":"Differential Neuronal Expression of Manganese Superoxide Dismutase in Alz-heimer\u2019s Disease","volume":"12","author":"Marcus","year":"2006","journal-title":"Med. Sci. Monit."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.2353\/ajpath.2006.051223","article-title":"\u03b2-Amyloid Mediated Nitration of Manganese Superoxide Dismutase","volume":"168","author":"Anantharaman","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.neuroscience.2008.01.044","article-title":"A neuronal model of Alzheimer\u2019s disease: An insight into the mechanisms of oxidative stress\u2013mediated mitochondrial injury","volume":"153","author":"Sompol","year":"2008","journal-title":"Neuroscience"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"6684","DOI":"10.1158\/0008-5472.CAN-11-1233","article-title":"Manganese Superoxide Dismutase Is a p53-Regulated Gene That Switches Cancers between Early and Advanced Stages","volume":"71","author":"Dhar","year":"2011","journal-title":"Cancer Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1158\/0008-5472.CAN-04-3835","article-title":"p53 Translocation to Mitochondria Precedes Its Nuclear Translocation and Targets Mitochondrial Oxidative Defense Protein-Manganese Superoxide Dismutase","volume":"65","author":"Zhao","year":"2005","journal-title":"Cancer Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s10863-016-9669-5","article-title":"p53 and mitochondrial dysfunction: Novel insight of neurodegenerative diseases","volume":"48","author":"Dai","year":"2016","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.freeradbiomed.2008.03.015","article-title":"Effects of oxidative and nitrosative stress in brain on p53 proapoptotic protein in amnestic mild cognitive impairment and Alzheimer disease","volume":"45","author":"Cenini","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1111\/j.1582-4934.2008.00163.x","article-title":"Elevated levels of pro-apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE, in brain from subjects with amnestic mild cognitive impairment and Alzheimer\u2019s disease","volume":"12","author":"Cenini","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3233\/JAD-2011-101425","article-title":"Increased Protein and Lipid Oxidative Damage in Mitochondria Isolated from Lymphocytes from Patients with Alzheimer\u2019s Disease: Insights into the Role of Oxidative Stress in Alzheimer\u2019s Disease and Initial Investigations into a Potential Biomarker for this Dementing Disorder","volume":"24","author":"Sultana","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.freeradbiomed.2013.08.001","article-title":"Lymphocyte mitochondria: Toward identification of peripheral biomarkers in the progression of Alzheimer disease","volume":"65","author":"Sultana","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s11011-011-9253-y","article-title":"Evaluation of respiratory chain activity in lymphocytes of patients with Alzheimer disease","volume":"26","author":"Feldhaus","year":"2011","journal-title":"Metab. Brain Dis."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0197-4580(03)00033-2","article-title":"Cytochrome c oxidase is decreased in Alzheimer\u2019s disease platelets","volume":"25","author":"Cardoso","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref_133","first-page":"19","article-title":"Strategy to reduce free radical species in Alzheimer\u2019s disease: An update of selected antioxidants","volume":"15","author":"Barone","year":"2014","journal-title":"Expert Rev. Neurother."},{"key":"ref_134","first-page":"1","article-title":"Mitochondrial Oxidative Damage in Aging and Alzheimer\u2019s Disease: Implications for Mitochondrially Targeted Antioxidant Therapeutics","volume":"2006","author":"Reddy","year":"2006","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1016\/j.addr.2008.04.015","article-title":"Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer\u2019s disease","volume":"60","author":"Maczurek","year":"2008","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1002\/biof.195","article-title":"Vitamin E in aging, dementia, and Alzheimer\u2019s disease","volume":"38","author":"Joshi","year":"2012","journal-title":"Biofactors"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1096\/fj.03-0961fje","article-title":"Early Vitamin E supplementation in young but not aged mice reduces A\u03b2 levels and amyloid deposition in a transgenic model of Alzheimer\u2019s disease","volume":"18","author":"Sung","year":"2003","journal-title":"FASEB J."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1001\/archneur.59.6.972","article-title":"Increase of Brain Oxidative Stress in Mild Cognitive Impairment","volume":"59","author":"Clark","year":"2002","journal-title":"Arch. Neurol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1016\/j.neurobiolaging.2011.11.019","article-title":"Tocopherols and tocotrienols plasma levels are associated with cognitive impairment","volume":"33","author":"Mangialasche","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1345\/aph.1G280","article-title":"Dementia and Alzheimer\u2019s Disease in Community-Dwelling Elders Taking Vitamin C and\/or Vitamin E","volume":"39","author":"Fillenbaum","year":"2005","journal-title":"Ann. Pharmacother."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1001\/jama.2013.282834","article-title":"Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease: The TEAM-AD VA cooperative randomized trial","volume":"311","author":"Dysken","year":"2014","journal-title":"JAMA"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.exger.2014.08.007","article-title":"Coenzyme Q10 and \u03b1-tocopherol reversed age-associated functional impairments in mice","volume":"58","author":"Shetty","year":"2014","journal-title":"Exp. Gerontol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S0891-5849(01)00595-0","article-title":"Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer\u2019s disease","volume":"31","author":"Kontush","year":"2001","journal-title":"Free Radic. Biol. Med."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.neuropharm.2010.04.005","article-title":"Oxidative stress in Alzheimer disease: A possibility for prevention","volume":"59","author":"Bonda","year":"2010","journal-title":"Neuropharmacology"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3233\/JAD-2007-12210","article-title":"Lipoic Acid and N-acetyl Cysteine Decrease Mitochondrial-Related Oxidative Stress in Alzheimer Disease Patient Fibroblasts","volume":"12","author":"Moreira","year":"2007","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.neuint.2004.07.008","article-title":"Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid: Implications for aging and age-related neurodegenerative disorders","volume":"46","author":"Poon","year":"2005","journal-title":"Neurochem. Int."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.freeradbiomed.2006.11.006","article-title":"Involvement of PI3K\/PKG\/ERK1\/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and \u03b1-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Implications for Alzheimer\u2019s disease","volume":"42","author":"Abdul","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.jns.2009.03.002","article-title":"The effect of acetyl-L-carnitine and R-\u03b1-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer\u2019s disease","volume":"283","author":"Shenk","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.bbamem.2003.11.012","article-title":"Metabolism and function of coenzyme Q","volume":"1660","author":"Turunen","year":"2004","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0891-5849(00)00307-5","article-title":"Regulation of ubiquinone metabolism","volume":"29","author":"Dallner","year":"2000","journal-title":"Free Radic. Biol. Med."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1139\/o92-061","article-title":"An analysis of the role of coenzyme Q in free radical generation and as an antioxidant","volume":"70","author":"Beyer","year":"1992","journal-title":"Biochem. Cell Biol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"28220","DOI":"10.1074\/jbc.M302297200","article-title":"Coenzyme Q10 Prevents Apoptosis by Inhibiting Mitochondrial Depolarization Independently of Its Free Radical Scavenging Property","volume":"278","author":"Formigli","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1023\/B:JOBB.0000041772.74810.92","article-title":"Mitochondrial Dysfunction and Oxidative Damage in Alzheimer\u2019s and Parkinson\u2019s Diseases and Coenzyme Q10as a Potential Treatment","volume":"36","author":"Beal","year":"2004","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.bbadis.2009.10.007","article-title":"Mitochondria: A therapeutic target in neurodegeneration","volume":"1802","author":"Moreira","year":"2010","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s12031-007-9033-7","article-title":"Coenzyme Q10 Attenuates \u03b2-Amyloid Pathology in the Aged Transgenic Mice with Alzheimer Presenilin 1 Mutation","volume":"34","author":"Yang","year":"2008","journal-title":"J. Mol. Neurosci."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"103409","DOI":"10.1016\/j.mcn.2019.103409","article-title":"The mitochondria-targeted antioxidant MitoQ inhibits memory loss, neuropathology, and extends lifespan in aged 3xTg-AD mice","volume":"101","author":"Young","year":"2019","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"14708","DOI":"10.1074\/jbc.M611463200","article-title":"Interaction of the Mitochondria-targeted Antioxidant MitoQ with Phospholipid Bilayers and Ubiquinone Oxidoreductases","volume":"282","author":"James","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s12035-009-8095-7","article-title":"Abnormal Mitochondrial Dynamics\u2014A Novel Therapeutic Target for Alzheimer\u2019s Disease?","volume":"41","author":"Su","year":"2010","journal-title":"Mol. Neurobiol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"37575","DOI":"10.1074\/jbc.M404003200","article-title":"Supplementation of Endothelial Cells with Mitochondria-targeted Antioxidants Inhibit Peroxide-induced Mitochondrial Iron Uptake, Oxidative Damage, and Apoptosis","volume":"279","author":"Dhanasekaran","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"15703","DOI":"10.1523\/JNEUROSCI.0552-11.2011","article-title":"The Mitochondria-Targeted Antioxidant MitoQ Prevents Loss of Spatial Memory Retention and Early Neuropathology in a Transgenic Mouse Model of Alzheimer\u2019s Disease","volume":"31","author":"McManus","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Chen, Q., Prior, M., Dargusch, R., Roberts, A., Riek, R., Eichmann, C., Chiruta, C., Akaishi, T., Abe, K., and Maher, P. (2011). A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer\u2019s Disease. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027865"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"e12715","DOI":"10.1111\/acel.12715","article-title":"The mitochondrial ATP synthase is a shared drug target for aging and dementia","volume":"17","author":"Goldberg","year":"2018","journal-title":"Aging Cell"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"937","DOI":"10.18632\/aging.100838","article-title":"A comprehensive multiomics approach toward understanding the relationship between aging and dementia","volume":"7","author":"Currais","year":"2015","journal-title":"Aging"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1021\/cn500051h","article-title":"Back to the Future with Phenotypic Screening","volume":"5","author":"Prior","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI13505","article-title":"Role of AMP-activated protein kinase in mechanism of metformin action","volume":"108","author":"Zhou","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.neurobiolaging.2005.01.004","article-title":"Insulin, insulin-degrading enzyme and amyloid-\u03b2 peptide in Alzheimer\u2019s disease: Review and hypothesis","volume":"27","author":"Qiu","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"6S95","DOI":"10.1016\/S1262-3636(03)72793-1","article-title":"Metformin inhibition of glycation processes","volume":"29","author":"Beisswenger","year":"2003","journal-title":"Diabetes Metab."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1161\/CIRCRESAHA.116.308445","article-title":"Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status","volume":"119","author":"Cameron","year":"2016","journal-title":"Circ. Res."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1021\/bi401444n","article-title":"Biomolecular Mode of Action of Metformin in Relation to Its Copper Binding Properties","volume":"53","author":"Erhardt","year":"2014","journal-title":"Biochemistry"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1042\/BJ20061520","article-title":"Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade","volume":"403","author":"Sanders","year":"2007","journal-title":"Biochem. J."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.stem.2012.03.016","article-title":"Metformin Activates an Atypical PKC-CBP Pathway to Promote Neurogenesis and Enhance Spatial Memory Formation","volume":"11","author":"Wang","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.neuropharm.2015.07.023","article-title":"Antidiabetic drugs restore abnormal transport of amyloid-\u03b2 across the blood\u2013brain barrier and memory impairment in db\/db mice","volume":"101","author":"Chen","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.yexcr.2016.08.013","article-title":"Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction","volume":"347","author":"Chiang","year":"2016","journal-title":"Exp. Cell Res."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/5\/386\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:52:22Z","timestamp":1760161942000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/5\/386"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,24]]},"references-count":173,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["life11050386"],"URL":"https:\/\/doi.org\/10.3390\/life11050386","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,24]]}}}