{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T02:31:32Z","timestamp":1792549892433,"version":"4.5.0"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"20","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS067525"],"award-info":[{"award-number":["NS067525"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["AG085688"],"award-info":[{"award-number":["AG085688"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["U19AG033655"],"award-info":[{"award-number":["U19AG033655"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008097","name":"Edward N. and Della L. Thome Memorial Foundation","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100008097","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"publisher","award":["Zenith Award"],"award-info":[{"award-number":["Zenith Award"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,19]]},"abstract":"<jats:p>\n                    Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer\u2019s disease (AD), yet its role in amyloid-beta (A\u03b2) pathology remains unclear. Here, we show that PARP1 activation drives A\u03b2 pathology and neurodegeneration. Using a sensitive enzyme-linked immunosorbent assay, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro, oligomeric A\u03b2\n                    <jats:sub>1-42<\/jats:sub>\n                    activated PARP1 and induced DNA damage, while genetic or pharmacological inhibition of PARP1 conferred neuroprotection. In vivo, PARP1 knockout in the 5XFAD mouse model of amyloidosis led to reduced amyloid plaque burden, preserved synaptic and neuronal integrity, attenuated glial activation and neuroinflammation, and rescued cognitive deficits. Mechanistically, PARP1 deficiency decreased amyloid precursor protein and BACE1 levels, altered \u03b3-secretase complex composition, and enhanced A\u03b2 degradation via neprilysin. These findings position PARP1 as a critical mediator of A\u03b2 toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2525028123","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:48:22Z","timestamp":1778867302000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer\u2019s disease model"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0620-7390","authenticated-orcid":false,"given":"Aanishaa","family":"Jhaldiyal","sequence":"first","affiliation":[{"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine","place":["Baltimore"]},{"name":"Department of Neurology, The 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Repon","family":"Khan","sequence":"additional","affiliation":[{"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine","place":["Baltimore"]},{"name":"Department of Neurology, The Johns Hopkins University School of Medicine","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1973-3258","authenticated-orcid":false,"given":"Justin","family":"Wang","sequence":"additional","affiliation":[{"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine","place":["Baltimore"]},{"name":"Department of Neurology, The Johns Hopkins University School of Medicine","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devanik","family":"Biswas","sequence":"additional","affiliation":[{"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, 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Jhaldiyal Data from \u201cPoly(ADP-ribose) polymerase 1 deficiency attenuates amyloid pathology neurodegeneration and cognitive decline in a familial Alzheimer disease model.\u201d Dryad. https:\/\/doi.org\/10.5061\/dryad.1rn8pk174. 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