{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:09:11Z","timestamp":1791929351585,"version":"4.3.4"},"reference-count":158,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer's Disease Reports"],"published-print":{"date-parts":[[2023,11,1]]},"abstract":"<jats:p>Oxidative stress, inflammation, and amyloid-\u03b2 are Alzheimer\u2019s disease (AD) hallmarks that cause each other and other AD hallmarks. Most amyloid-\u03b2-lowering, antioxidant, anti-inflammatory, and antimicrobial AD clinical trials failed; none stopped or reversed AD. Although signs suggest an infectious etiology, no pathogen accumulated consistently in AD patients. Neuropathology, neuronal cell culture, rodent, genome-wide association, epidemiological, biomarker, and clinical studies, plus analysis using Hill causality criteria and revised Koch\u2019s postulates, indicate that the virus-like oxidative damage-associated molecular-pattern (DAMP) cytosolic and cell-free nucleic acids accumulated in AD patients\u2019 brains likely drive neuroinflammation, synaptotoxicity, and neurotoxicity. Cytosolic oxidatively-damaged mitochondrial DNA accumulated outside mitochondria dose-dependently in preclinical AD and AD patients\u2019 hippocampal neurons, and in AD patients\u2019 neocortical neurons but not cerebellar neurons or glia. In oxidatively-stressed neural cells and rodents\u2019 brains, cytosolic oxidatively-damaged mitochondrial DNA accumulated and increased antiviral and inflammatory proteins, including cleaved caspase-1, interleukin-1\u03b2, and interferon-\u03b2. Cytosolic double-stranded RNA and DNA are DAMPs that induce antiviral interferons and\/or inflammatory proteins by oligomerizing with various innate-immune pattern-recognition receptors, e.g., cyclic GMP-AMP synthase and the nucleotide-binding-oligomerization-domain-like-receptor-pyrin-domain-containing-3 inflammasome. In oxidatively-stressed neural cells, cytosolic oxidatively-damaged mitochondrial DNA caused synaptotoxicity and neurotoxicity. Depleting mitochondrial DNA prevented these effects. Additionally, cell-free nucleic acids accumulated in AD patients\u2019 blood, extracellular vesicles, and senile plaques. Injecting cell-free nucleic acids bound to albumin oligomers into wild-type mice\u2019s hippocampi triggered antiviral interferon-\u03b2 secretion; interferon-\u03b2 injection caused synapse degeneration. Deoxyribonuclease-I treatment appeared to improve a severe-AD patient\u2019s Mini-Mental Status Exam by 15 points. Preclinical and clinical studies of deoxyribonuclease-I and a ribonuclease for AD should be prioritized.<\/jats:p>","DOI":"10.3233\/adr-220047","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T10:06:01Z","timestamp":1670580361000},"page":"1-19","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":11,"title":["Virus-Like Cytosolic and Cell-Free Oxidatively Damaged Nucleic Acids Likely Drive Inflammation, Synapse Degeneration, and Neuron Death in Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"7","author":[{"given":"Owen Davis","family":"Sanders","sequence":"first","affiliation":[{"name":"Nebraska Medical Center, Omaha, NE, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"ref001","doi-asserted-by":"publisher","DOI":"10.1080\/01677063.2021.1954641"},{"key":"ref002","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.08.019"},{"key":"ref003","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.30"},{"key":"ref004","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-021-00813-8"},{"key":"ref005","doi-asserted-by":"publisher","DOI":"10.1002\/gps.3846"},{"key":"ref006","doi-asserted-by":"publisher","DOI":"10.3233\/ADR-210301"},{"key":"ref007","doi-asserted-by":"publisher","DOI":"10.1016\/bs.irn.2020.03.022"},{"key":"ref008","first-page":"2","volume":"3","author":"Broxmeyer L","year":"2017","journal-title":"J Mol Path Epidemiol"},{"key":"ref009","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.06.3040"},{"key":"ref010","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00159"},{"key":"ref011","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciab993"},{"key":"ref012","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160451"},{"key":"ref013","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2018.00362"},{"key":"ref014","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.05.023"},{"key":"ref015","doi-asserted-by":"publisher","DOI":"10.1002\/path.2449"},{"key":"ref016","doi-asserted-by":"publisher","DOI":"10.1142\/S0219720020500122"},{"key":"ref017","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines9060679"},{"key":"ref018","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-09-03017.2001"},{"key":"ref019","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2011.08.003"},{"key":"ref020","doi-asserted-by":"publisher","DOI":"10.2174\/1567205015666180223093020"},{"key":"ref021","doi-asserted-by":"publisher","DOI":"10.1172\/JCI133737"},{"key":"ref022","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(199902)45:2<174::AID-ANA7>3.0.CO;2-E"},{"key":"ref023","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-022-01347-2"},{"key":"ref024","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-018-0061-5"},{"key":"ref025","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-170634"},{"key":"ref026","doi-asserted-by":"publisher","DOI":"10.1172\/JCI135026"},{"key":"ref027","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.08.018"},{"key":"ref028","first-page":"1859","volume":"25","author":"Bis JC","year":"2020","journal-title":"MolPsychiatry"},{"key":"ref029","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15287"},{"key":"ref030","first-page":"3","volume":"2","author":"Guglielmotto M","year":"2010","journal-title":"Front Aging Neurosci"},{"key":"ref031","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/375968"},{"key":"ref032","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0235335"},{"key":"ref033","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-1229-z"},{"key":"ref034","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.581882"},{"key":"ref035","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21176298"},{"key":"ref036","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23955"},{"key":"ref037","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2015.12.011"},{"key":"ref038","doi-asserted-by":"publisher","DOI":"10.1186\/s13256-016-0931-6"},{"key":"ref039","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410360510"},{"key":"ref040","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03615.x"},{"key":"ref041","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03053.x"},{"key":"ref042","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2022.10.005"},{"key":"ref043","doi-asserted-by":"publisher","DOI":"10.1038\/nature11729"},{"key":"ref044","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-210268"},{"key":"ref045","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.1c00831"},{"key":"ref046","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2020.101192"},{"key":"ref047","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.701282"},{"key":"ref048","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S295706"},{"key":"ref049","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1579-0"},{"key":"ref050","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0372-z"},{"key":"ref051","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00480"},{"key":"ref052","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-017-0308-0"},{"key":"ref053","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2014.00022"},{"key":"ref054","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2011.11.031"},{"key":"ref055","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-9961(03)00086-X"},{"key":"ref056","author":"Martorell P","year":"2020","journal-title":"BonnBrain3 Meeting"},{"key":"ref057","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.624597"},{"key":"ref058","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2017.08.012"},{"key":"ref059","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(92)90971-B"},{"key":"ref060","doi-asserted-by":"publisher","DOI":"10.2147\/NDT.S157099"},{"key":"ref061","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2016.1239003"},{"key":"ref062","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-019-1639-5"},{"key":"ref063","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2011.01.003"},{"key":"ref064","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12286"},{"key":"ref065","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02329-2"},{"key":"ref066","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1789.2006.00701.x"},{"key":"ref067","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600699"},{"key":"ref068","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.100"},{"key":"ref069","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.139"},{"key":"ref070","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02188"},{"key":"ref071","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23452-x"},{"key":"ref072","doi-asserted-by":"publisher","DOI":"10.1097\/01.jnen.0000240476.73532.b0"},{"key":"ref073","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0774-19.2019"},{"key":"ref074","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0124-15.2016"},{"key":"ref075","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2010-091681"},{"key":"ref076","doi-asserted-by":"publisher","DOI":"10.2174\/1567205011666140302200902"},{"key":"ref077","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1922-z"},{"key":"ref078","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-06377-8"},{"key":"ref079","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.05.024"},{"key":"ref080","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-2-18"},{"key":"ref081","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-010-0666-1"},{"key":"ref082","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01629"},{"key":"ref083","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009505"},{"key":"ref084","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160415"},{"key":"ref085","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat1022"},{"key":"ref086","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms9061301"},{"key":"ref087","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2007-12408"},{"key":"ref088","doi-asserted-by":"publisher","DOI":"10.1006\/abio.2000.4719"},{"key":"ref089","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.106.093559"},{"key":"ref090","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2013.01.007"},{"key":"ref091","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410410211"},{"key":"ref092","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2017.03.011"},{"key":"ref093","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1275-5"},{"key":"ref094","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05077-9"},{"key":"ref095","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02083-1"},{"key":"ref096","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601694"},{"key":"ref097","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2017.54"},{"key":"ref098","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(89)90843-4"},{"key":"ref099","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(97)00849-4"},{"key":"ref100","doi-asserted-by":"publisher","DOI":"10.1007\/BF00685397"},{"key":"ref101","doi-asserted-by":"publisher","DOI":"10.1007\/BF00687336"},{"key":"ref102","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0536-8"},{"key":"ref103","doi-asserted-by":"publisher","DOI":"10.1186\/s12877-020-01644-2"},{"key":"ref104","doi-asserted-by":"publisher","DOI":"10.1016\/j.pscychresns.2008.04.003"},{"key":"ref105","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.2016152244"},{"key":"ref106","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2016.06.006"},{"key":"ref107","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-022-00522-2"},{"key":"ref108","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13601-y"},{"key":"ref109","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-161141"},{"key":"ref110","doi-asserted-by":"publisher","DOI":"10.1126\/science.159.3813.390"},{"key":"ref111","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1985.248.1.C12"},{"key":"ref112","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2014.44"},{"key":"ref113","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12206"},{"key":"ref114","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2010.02.016"},{"key":"ref115","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.08.016"},{"key":"ref116","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtemb.2016.06.005"},{"key":"ref117","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2007-12107"},{"key":"ref118","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2010-101083"},{"key":"ref119","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2005.11.002"},{"key":"ref120","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.9.1.18"},{"key":"ref121","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65396-5"},{"key":"ref122","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12168"},{"key":"ref123","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2016.02.030"},{"key":"ref124","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02459-1"},{"key":"ref125","first-page":"135","volume":"2","author":"Morris GP","year":"2014","journal-title":"Acta Neuropathol Commun"},{"key":"ref126","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-006-0071-y"},{"key":"ref127","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0114041"},{"key":"ref128","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1698-16.2016"},{"key":"ref129","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"ref130","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv278"},{"key":"ref131","unstructured":"KarlRaimund Popper (2002) The Logic of Scientific Discovery, Psychology Press."},{"key":"ref132","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.58.12.1791"},{"key":"ref133","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e318232a379"},{"key":"ref134","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2008.11.006"},{"key":"ref135","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181772794"},{"key":"ref136","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.104795"},{"key":"ref137","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2635903100"},{"key":"ref138","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/59.11.1011"},{"key":"ref139","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2016.06.004"},{"key":"ref140","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2002.0542"},{"key":"ref141","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0221669"},{"key":"ref142","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.01.012"},{"key":"ref143","doi-asserted-by":"publisher","DOI":"10.1042\/bse0560181"},{"key":"ref144","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00244"},{"key":"ref145","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000263"},{"key":"ref146","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/11.2.283"},{"key":"ref147","doi-asserted-by":"publisher","DOI":"10.1590\/S0100-879X2009007500001"},{"key":"ref148","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt671"},{"key":"ref149","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/14.1.95"},{"key":"ref150","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24709"},{"key":"ref151","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003974"},{"key":"ref152","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003794"},{"key":"ref153","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)48474-8"},{"key":"ref154","doi-asserted-by":"publisher","DOI":"10.3390\/biom10071036"},{"key":"ref155","doi-asserted-by":"publisher","DOI":"10.1002\/art.41489"},{"key":"ref156","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202100639"},{"key":"ref157","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1101874108"},{"key":"ref158","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2020.1840"}],"container-title":["Journal of Alzheimer's Disease Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3233\/ADR-220047","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.3233\/ADR-220047","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3233\/ADR-220047","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T09:57:21Z","timestamp":1777370241000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.3233\/ADR-220047"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,9]]},"references-count":158,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,11,1]]}},"alternative-id":["10.3233\/ADR-220047"],"URL":"https:\/\/doi.org\/10.3233\/adr-220047","relation":{},"ISSN":["2542-4823","2542-4823"],"issn-type":[{"value":"2542-4823","type":"print"},{"value":"2542-4823","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,9]]}}}