{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:18:24Z","timestamp":1788873504372,"version":"build-2803163510"},"reference-count":81,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T00:00:00Z","timestamp":1754956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione","award":["CUPB84I18000540002"],"award-info":[{"award-number":["CUPB84I18000540002"]}]},{"name":"Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione","award":["CUP H99J21017840005"],"award-info":[{"award-number":["CUP H99J21017840005"]}]},{"name":"C.I.R.E.M.I.C (Research Center of Excellence for Neurodegenerative Diseases and Bari), University of Bari Aldo Moro","award":["CUPB84I18000540002"],"award-info":[{"award-number":["CUPB84I18000540002"]}]},{"name":"C.I.R.E.M.I.C (Research Center of Excellence for Neurodegenerative Diseases and Bari), University of Bari Aldo Moro","award":["CUP H99J21017840005"],"award-info":[{"award-number":["CUP H99J21017840005"]}]},{"name":"BIO-MAD-SEEDS","award":["CUPB84I18000540002"],"award-info":[{"award-number":["CUPB84I18000540002"]}]},{"name":"BIO-MAD-SEEDS","award":["CUP H99J21017840005"],"award-info":[{"award-number":["CUP H99J21017840005"]}]},{"name":"Fondi di Ateneo FondoQualit\u00e0Ricerca2024 (University of Bari)","award":["CUPB84I18000540002"],"award-info":[{"award-number":["CUPB84I18000540002"]}]},{"name":"Fondi di Ateneo FondoQualit\u00e0Ricerca2024 (University of Bari)","award":["CUP H99J21017840005"],"award-info":[{"award-number":["CUP H99J21017840005"]}]},{"name":"MIUR-FFABR","award":["CUPB84I18000540002"],"award-info":[{"award-number":["CUPB84I18000540002"]}]},{"name":"MIUR-FFABR","award":["CUP H99J21017840005"],"award-info":[{"award-number":["CUP H99J21017840005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondrial oxidative stress and neuroinflammation are involved in the onset and progression of Alzheimer\u2019s disease (AD). Novel reliable, circulating biomarkers related to these processes were searched in cerebrospinal fluid (CSF) and plasma samples. Paired CSF and plasma samples from 20 subjective memory complaints (SMC) subjects, 20 mild cognitive impairment (MCI) due to AD subjects, and 20 Alzheimer\u2019s dementia (ADd) patients were analyzed. Protein amounts of manganese-containing superoxide dismutase 2 (SOD2), cell-free mitochondrial DNA (cf-mtDNA) level, DNase I, and matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) activities were determined. As for SOD2, an MCI male-specific significant increase in both biofluids and an ADd male-specific significant decrease in plasma were found. No significant differences were demonstrated in cf-mtDNA level. An ADd-specific significant increase in plasma DNase I and MMP-2 activities was found. A SMC female-specific significant higher value in CSF MMP-9 activity in comparison to male counterparts was demonstrated. The present results suggest a male patient-specific (MCI and ADd) regulation of SOD2 expression in plasma and support an ADd-specific increase in plasma DNase I and MMP-2 activities. Therefore, the potential of SOD2 amount, DNase I, and MMP-2 activities in plasma as new markers of ADd should be explored. The SMC female-specific high activity of MMP-9 might contribute to AD female-sex bias.<\/jats:p>","DOI":"10.3390\/ijms26167792","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T07:45:31Z","timestamp":1755071131000},"page":"7792","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Reliable New Biomarkers of Mitochondrial Oxidative Stress and Neuroinflammation in Cerebrospinal Fluid and Plasma from Alzheimer\u2019s Disease Patients: A Pilot Study"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4190-3875","authenticated-orcid":false,"given":"Rosa","family":"Di Lorenzo","sequence":"first","affiliation":[{"name":"Department of Biosciences Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Zecca","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari Aldo Moro, \u201cPia Fondazione Cardinale G. Panico\u201d, 73039 Tricase, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4403-2317","authenticated-orcid":false,"given":"Guglielmina","family":"Chimienti","sequence":"additional","affiliation":[{"name":"Department of Biosciences Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6971-5416","authenticated-orcid":false,"given":"Tiziana","family":"Latronico","sequence":"additional","affiliation":[{"name":"Department of Biosciences Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5692-9335","authenticated-orcid":false,"given":"Grazia Maria","family":"Liuzzi","sequence":"additional","affiliation":[{"name":"Department of Biosciences Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9148-3129","authenticated-orcid":false,"given":"Vito","family":"Pesce","sequence":"additional","affiliation":[{"name":"Department of Biosciences Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9952-4247","authenticated-orcid":false,"given":"Maria Teresa","family":"Dell\u2019Abate","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari Aldo Moro, \u201cPia Fondazione Cardinale G. Panico\u201d, 73039 Tricase, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Borlizzi","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari Aldo Moro, \u201cPia Fondazione Cardinale G. Panico\u201d, 73039 Tricase, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9366-1582","authenticated-orcid":false,"given":"Alessia","family":"Giugno","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari Aldo Moro, \u201cPia Fondazione Cardinale G. Panico\u201d, 73039 Tricase, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Urso","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari Aldo Moro, \u201cPia Fondazione Cardinale G. Panico\u201d, 73039 Tricase, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Logroscino","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari Aldo Moro, \u201cPia Fondazione Cardinale G. Panico\u201d, 73039 Tricase, Italy"},{"name":"Department of Translational Biomedicine and Neuroscience (DiBraiN), University of Bari Aldo Moro, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2006-1076","authenticated-orcid":false,"given":"Angela Maria Serena","family":"Lezza","sequence":"additional","affiliation":[{"name":"Department of Biosciences Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R12","DOI":"10.1093\/hmg\/ddq160","article-title":"Molecular mechanisms of neurodegeneration in Alzheimer\u2019s disease","volume":"19","author":"Crews","year":"2010","journal-title":"Hum. Mol. Genet."},{"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":"281","DOI":"10.1007\/s10522-015-9618-4","article-title":"Mitochondrial dysfunction: The missing link between aging and sporadic Alzheimer\u2019s disease","volume":"17","author":"Grimm","year":"2016","journal-title":"Biogerontology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer\u2019s Disease: Causes and Treatment. Molecules, 25.","DOI":"10.3390\/molecules25245789"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/s10787-023-01173-5","article-title":"Antioxidants: An approach for restricting oxidative stress induced neurodegeneration in Alzheimer\u2019s disease","volume":"31","author":"Dubey","year":"2023","journal-title":"Inflammopharmacology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3691","DOI":"10.1016\/j.molcel.2021.08.018","article-title":"Redox metabolism: ROS as specific molecular regulators of cell signaling and function","volume":"81","author":"Lennicke","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.biocel.2006.07.001","article-title":"Free radicals and antioxidants in normal physiological functions and human disease","volume":"39","author":"Valko","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Abate, G., Vezzoli, M., Sandri, M., Rungratanawanich, W., Memo, M., and Uberti, D. (2020). Mitochondria and cellular redox state on the route from ageing to Alzheimer\u2019s disease. Mech. Ageing Dev., 192.","DOI":"10.1016\/j.mad.2020.111385"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1007\/s11357-012-9465-z","article-title":"Age- and calorie restriction-related changes in rat brain mitochondrial DNA and TFAM binding","volume":"35","author":"Picca","year":"2013","journal-title":"Age"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Picca, A., Pesce, V., Fracasso, F., Joseph, A.M., Leeuwenburgh, C., and Lezza, A.M.S. (2013). Aging and calorie restriction oppositely affect mitochondrial biogenesis through TFAM binding at both origins of mitochondrial DNA replication in rat liver. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074644"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/alz.12683","article-title":"The role of mitochondrial dysfunction in Alzheimer\u2019s disease pathogenesis","volume":"19","author":"Ashleigh","year":"2023","journal-title":"Alzheimers Dement."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.mehy.2003.12.045","article-title":"A \u201cmitochondrial cascade hypothesis\u201d for sporadic Alzheimer\u2019s disease","volume":"63","author":"Swerdlow","year":"2004","journal-title":"Med. Hypotheses"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1089\/ars.2011.4400","article-title":"Insights into mitochondrial dysfunction: Aging, amyloid-beta, and tau-A deleterious trio","volume":"16","author":"Schmitt","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1080\/15622975.2017.1375556","article-title":"Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry","volume":"19","author":"Lewczuk","year":"2018","journal-title":"World. J. Biol. Psychiatry."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/S1474-4422(21)00066-1","article-title":"Clinical diagnosis of Alzheimer\u2019s disease: Recommendations of the International Working Group","volume":"20","author":"Dubois","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association Report (2021). 2021 Alzheimer\u2019s disease facts and figures. Alzheimers Dement., 17, 327\u2013406.","DOI":"10.1002\/alz.12328"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Aisen, P.S., Cummings, J., Jack, C.R., Morris, J.C., Sperling, R., Fr\u00f6lich, L., Jones, R.W., Dowsett, S.A., Matthews, B.R., and Raskin, J. (2017). On the path to 2025: Understanding the Alzheimer\u2019s disease continuum. Alzheimers Res. Ther., 9.","DOI":"10.1186\/s13195-017-0283-5"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA Research Framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, J., Gu, B.J., Masters, C.L., and Wang, Y.J. (2017). A systemic view of Alzheimer disease-insights from amyloid-\u03b2 metabolism beyond the brain. Nat. Rev. Neurol., 13.","DOI":"10.1038\/nrneurol.2017.111"},{"key":"ref_20","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_21","doi-asserted-by":"crossref","unstructured":"Picca, A., Lezza, A.M.S., Leeuwenburgh, C., Pesce, V., Calvani, R., Landi, F., Bernabei, R., and Marzetti, E. (2017). Fueling Inflamm-Aging through Mitochondrial Dysfunction: Mechanisms and Molecular Targets. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18050933"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chimienti, G., Picca, A., Fracasso, F., Russo, F., Orlando, A., Riezzo, G., Leeuwenburgh, C., Pesce, V., and Lezza, A.M.S. (2021). The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041665"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.cardiores.2005.01.026","article-title":"PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells","volume":"66","author":"Valle","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.cell.2006.09.024","article-title":"Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators","volume":"127","author":"Drori","year":"2006","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1016\/j.freeradbiomed.2012.09.014","article-title":"Redox regulation of mitochondrial biogenesis","volume":"53","author":"Piantadosi","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0304-3940(98)00469-8","article-title":"Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer\u2019s disease","volume":"250","author":"Borrello","year":"1998","journal-title":"Neurosci. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1523\/JNEUROSCI.0295-20.2020","article-title":"Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer\u2019s Neuropathology","volume":"41","author":"Fracassi","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wang, H., Dey, K.K., Chen, P.C., Li, Y., Niu, M., Cho, J.H., Wang, X., Bai, B., Jiao, Y., and Chepyala, S.R. (2020). Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer\u2019s disease. Mol. Neurodegener., 15.","DOI":"10.1186\/s13024-020-00384-6"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s43587-023-00550-7","article-title":"Cerebrospinal fluid proteomics in patients with Alzheimer\u2019s disease reveals five molecular subtypes with distinct genetic risk profiles","volume":"4","author":"Tijms","year":"2024","journal-title":"Nat. Aging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1016\/j.cmet.2022.10.008","article-title":"Mitochondrial signal transduction","volume":"34","author":"Picard","year":"2022","journal-title":"Cell Metab."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Giordano, L., Gregory, A.D., P\u00e9rez Verdaguer, M., Ware, S.A., Harvey, H., DeVallance, E., Brzoska, T., Sundd, P., Zhang, Y., and Sciurba, F.C. (2022). Extracellular Release of Mitochondrial DNA: Triggered by Cigarette Smoke and Detected in COPD. Cells, 11.","DOI":"10.3390\/cells11030369"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5784","DOI":"10.1111\/ejn.15828","article-title":"Exosome-associated mitochondrial DNA from patients with myalgic encephalomyelitis\/chronic fatigue syndrome stimulates human microglia to release IL-1\u03b2","volume":"56","author":"Tsilioni","year":"2022","journal-title":"Eur. J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Borah, S., Mishra, R., Dey, S., Suchanti, S., Bhowmick, N.A., Giri, B., and Haldar, S. (2023). Corrigendum to \u201cPrognostic value of circulating mitochondrial DNA in prostate cancer and underlying mechanism\u201d [Mitochondrion 71 (2023) 40\u201349]. Mitochondrion, 71.","DOI":"10.1016\/j.mito.2023.05.005"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Gorham, I.K., Barber, R.C., Jones, H.P., and Phillips, N.R. (2023). Mitochondrial SOS: How mtDNA may act as a stress signal in Alzheimer\u2019s disease. Alzheimers Res. Ther., 15.","DOI":"10.1186\/s13195-023-01322-6"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Grazioli, S., and Pugin, J. (2018). Mitochondrial Damage-Associated Molecular Patterns: From Inflammatory Signaling to Human Diseases. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00832"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Podlesniy, P., Llorens, F., Puigr\u00f2s, M., Serra, N., Sep\u00falveda-Falla, D., Schmidt, C., Hermann, P., Zerr, I., and Trullas, R. (2020). Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176298"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Klein, H.U., Trumpff, C., Yang, H.S., Lee, A.J., Picard, M., Bennett, D.A., and De Jager, P.L. (2021). Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer\u2019s disease brain. Mol. Neurodegener., 16.","DOI":"10.1186\/s13024-021-00495-8"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.ajhg.2020.01.008","article-title":"The Biology of Cell-free DNA Fragmentation and the Roles of DNASE1, DNASE1L3, and DFFB","volume":"106","author":"Han","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.freeradbiomed.2021.08.019","article-title":"The oxidatively damaged DNA and amyloid-\u03b2 oligomer hypothesis of Alzheimer\u2019s disease","volume":"179","author":"Sanders","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Arvanitaki, E.S., Goulielmaki, E., Gkirtzimanaki, K., Niotis, G., Tsakani, E., Nenedaki, E., Rouska, I., Kefalogianni, M., Xydias, D., and Kalafatakis, I. (2024). Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage. Proc. Natl. Acad. Sci. USA, 121.","DOI":"10.1073\/pnas.2317402121"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/ADR-220047","article-title":"Virus-Like Cytosolic and Cell-Free Oxidatively Damaged Nucleic Acids Likely Drive Inflammation, Synapse Degeneration, and Neuron Death in Alzheimer\u2019s Disease","volume":"7","author":"Sanders","year":"2023","journal-title":"J. Alzheimers Dis. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Picca, A., Calvani, R., Coelho-Junior, H.J., Landi, F., Bernabei, R., and Marzetti, E. (2020). Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration. Antioxidants, 9.","DOI":"10.3390\/antiox9080647"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Deus, C.M., Tavares, H., Beatriz, M., Mota, S., and Lopes, C. (2022). Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders. Cells, 11.","DOI":"10.20944\/preprints202207.0078.v2"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Behl, T., Kaur, G., Sehgal, A., Bhardwaj, S., Singh, S., Buhas, C., Judea-Pusta, C., Uivarosan, D., Munteanu, M.A., and Bungau, S. (2021). Multifaceted Role of Matrix Metalloproteinases in Neurodegenerative Diseases: Pathophysiological and Therapeutic Perspectives. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031413"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neurobiolaging.2023.05.012","article-title":"Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals","volume":"131","author":"Aksnes","year":"2023","journal-title":"Neurobiol. Aging"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1007\/s12035-024-04315-0","article-title":"The Link Between Matrix Metalloproteinases and Alzheimer\u2019s Disease Pathophysiology","volume":"62","author":"Radosinska","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Ciccone, L., Vandooren, J., Nencetti, S., and Orlandini, E. (2021). Natural Marine and Terrestrial Compounds as Modulators of Matrix Metalloproteinases-2 (MMP-2) and MMP-9 in Alzheimer\u2019s Disease. Pharmaceuticals, 14.","DOI":"10.3390\/ph14020086"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Udeh-Momoh, C., and Watermeyer, T. (2021). Female Brain Health and Endocrine Research (FEMBER) consortium. Female specific risk factors for the development of Alzheimer\u2019s disease neuropathology and cognitive impairment: Call for a precision medicine approach. Ageing Res. Rev., 71.","DOI":"10.1016\/j.arr.2021.101459"},{"key":"ref_49","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_50","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s10863-017-9718-8","article-title":"Manganese superoxide dismutase (SOD2): Is there a center in the universe of mitochondrial redox signaling?","volume":"49","author":"Zou","year":"2017","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Costa, G., Caputi, F.F., Serra, M., Simola, N., Rullo, L., Stamatakos, S., Sanna, F., Germain, M., Martinoli, M.G., and Candeletti, S. (2021). Activation of Antioxidant and Proteolytic Pathways in the Nigrostriatal Dopaminergic System After 3,4-Methylenedioxymethamphetamine Administration: Sex-Related Differences. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.713486"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/ana.26946","article-title":"Irisin Levels in Cerebrospinal Fluid Correlate with Biomarkers and Clinical Dementia Scores in Alzheimer Disease","volume":"96","author":"Dicarlo","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Picca, A., Guerra, F., Calvani, R., Coelho-J\u00fanior, H.J., Landi, F., Bucci, C., and Marzetti, E. (2023). Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241813835"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1002\/ana.23955","article-title":"Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease","volume":"74","author":"Podlesniy","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"192.e1","DOI":"10.1016\/j.neurobiolaging.2016.12.009","article-title":"Cerebrospinal fluid mitochondrial DNA in the Alzheimer\u2019s disease continuum","volume":"53","author":"Alcolea","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Mohanty, T., Fisher, J., Bakochi, A., Neumann, A., Cardoso, J.F.P., Karlsson, C.A.Q., Pavan, C., Lundgaard, I., Nilson, B., and Reinstrup, P. (2019). Neutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis. Nat. Commun., 10.","DOI":"10.1038\/s41467-019-09040-0"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1097\/TA.0000000000001919","article-title":"Reduced deoxyribonuclease enzyme activity in response to high postinjury mitochondrial DNA concentration provides a therapeutic target for Systemic Inflammatory Response Syndrome","volume":"85","author":"McIlroy","year":"2018","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Tetz, V., and Tetz, G. (2016). Effect of deoxyribonuclease I treatment for dementia in end-stage Alzheimer\u2019s disease: A case report. J. Med. Case Rep., 10.","DOI":"10.1186\/s13256-016-0931-6"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1111\/bph.14593","article-title":"Targeting amyloid clearance in Alzheimer\u2019s disease as a therapeutic strategy","volume":"176","author":"Nalivaeva","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"10939","DOI":"10.1523\/JNEUROSCI.2085-06.2006","article-title":"Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism","volume":"26","author":"Yin","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1111\/jnc.15762","article-title":"Experimental approaches for altering the expression of Abeta-degrading enzymes","volume":"164","author":"Loeffler","year":"2023","journal-title":"J. Neurochem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1017\/S1041610210000827","article-title":"Matrix metalloproteinases in peripheral blood and cerebrospinal fluid in patients with Alzheimer\u2019s disease","volume":"22","author":"Horstmann","year":"2010","journal-title":"Int. Psychogeriatr."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Whelan, C.D., Mattsson, N., Nagle, M.W., Vijayaraghavan, S., Hyde, C., Janelidze, S., Stomrud, E., Lee, J., Fitz, L., and Samad, T.A. (2019). Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer\u2019s disease. Acta Neuropathol. Commun., 7.","DOI":"10.1186\/s40478-019-0795-2"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0197-0186(03)00004-4","article-title":"Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer\u2019s disease","volume":"43","author":"Lorenzl","year":"2003","journal-title":"Neurochem. Int."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1017\/S1041610207005790","article-title":"Profiles of matrix metalloproteinases and their inhibitors in plasma of patients with dementia","volume":"20","author":"Lorenzl","year":"2008","journal-title":"Int. Psychogeriatr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1002\/acn3.51155","article-title":"Elevated matrix metalloproteinase-9 levels in neuronal extracellular vesicles in Alzheimer\u2019s disease","volume":"7","author":"Gu","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Tsiknia, A.A., Sundermann, E.E., Reas, E.T., Edland, S.D., Brewer, J.B., Galasko, D., and Banks, S.J. (2022). Alzheimer\u2019s Disease Neuroimaging Initiative. Sex differences in Alzheimer\u2019s disease: Plasma MMP-9 and markers of disease severity. Alzheimers Res. Ther., 14.","DOI":"10.1186\/s13195-022-01106-4"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.mcn.2012.02.005","article-title":"Estrogen activates matrix metalloproteinases-2 and -9 to increase beta amyloid degradation","volume":"49","author":"Merlo","year":"2012","journal-title":"Mol. Cell Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0006-8993(03)02344-8","article-title":"Beta-amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes","volume":"970","author":"Deb","year":"2003","journal-title":"Brain Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/S0140-6736(07)61602-X","article-title":"The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for reporting observational studies","volume":"370","author":"Altman","year":"2007","journal-title":"Lancet"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (DSM-5\u00ae), American Psychiatric Publishing. [5th ed.].","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The diagnosis of dementia due to Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"McKhann","year":"2011","journal-title":"Alzheimers Dement."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.jalz.2014.01.001","article-title":"Subjective Cognitive Decline Initiative (SCD-I) Working Group. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer\u2019s disease","volume":"10","author":"Jessen","year":"2014","journal-title":"Alzheimers Dement."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"(1991). World Medical Association Declaration of Helsinki. Law Med. Health Care, 19, 264\u2013265.","DOI":"10.1111\/j.1748-720X.1991.tb01824.x"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jalz.2011.07.004","article-title":"Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer\u2019s disease diagnosis: A consensus paper from the Alzheimer\u2019s Biomarkers Standardization Initiative","volume":"8","author":"Vanderstichele","year":"2012","journal-title":"Alzheimers Dement."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/978-1-4939-7778-9_7","article-title":"Biomarkers in Cerebrospinal Fluid: Analysis of Cell-Free Circulating Mitochondrial DNA by Digital PCR","volume":"1768","author":"Podlesniy","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Chimienti, G., Russo, F., Bianco, A., Maqoud, F., De Virgilio, C., Galeano, G., Orlando, A., Riezzo, G., D\u2019Attoma, B., and Ignazzi, A. (2024). Effect of a 12-Week Walking Program Monitored by Global Physical Capacity Score (GPCS) on Circulating Cell-Free mtDNA and DNase Activity in Patients with Irritable Bowel Syndrome. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084293"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Ondracek, A.S., Aszlan, A., Schmid, M., Lenz, M., Mangold, A., Artner, T., Emich, M., Fritzer-Szekeres, M., Strametz-Juranek, J., and Lang, I.M. (2022). Physical Exercise Promotes DNase Activity Enhancing the Capacity to Degrade Neutrophil Extracellular Traps. Biomedicines, 10.","DOI":"10.3390\/biomedicines10112849"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.ab.2012.08.015","article-title":"Comparison of Stain-Free gels with traditional immunoblot loading control methodology","volume":"430","author":"Colella","year":"2012","journal-title":"Anal. Biochem."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Zuccal\u00e0, P., Latronico, T., Marocco, R., Savinelli, S., Vita, S., Mengoni, F., Tieghi, T., Borgo, C., Kertusha, B., and Carraro, A. (2022). Longitudinal Assessment of Multiple Immunological and Inflammatory Parameters during Successful DAA Therapy in HCV Monoinfected and HIV\/HCV Coinfected Subjects. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911936"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Zingaropoli, M.A., Iannetta, M., Piermatteo, L., Pasculli, P., Latronico, T., Mazzuti, L., Campogiani, L., Duca, L., Ferraguti, G., and De Michele, M. (2022). Neuro-Axonal Damage and Alteration of Blood-Brain Barrier Integrity in COVID-19 Patients. Cells, 11.","DOI":"10.3390\/cells11162480"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7792\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:25:54Z","timestamp":1760034354000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7792"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,12]]},"references-count":81,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26167792"],"URL":"https:\/\/doi.org\/10.3390\/ijms26167792","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,12]]}}}