{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T22:12:49Z","timestamp":1791670369851,"version":"4.3.4"},"reference-count":54,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"45","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,11,7]]},"abstract":"<jats:p>Impaired clearance of amyloid-\u03b2 (A\u03b2) contributes to Alzheimer\u2019s disease (AD) pathogenesis, but its upstream modulators remain poorly defined. We report secreted Dickkopf (DKK) proteins\u2014DKK1 through DKK4\u2014as previously unrecognized ligands of low-density lipoprotein receptor\u2013related protein 1 (LRP1), a principal A\u03b2 clearance receptor. Analyses of cells derived from a patient with AD, postmortem tissue, and 5\u00d7FAD mice reveal that DKK1 and DKK3 are elevated in AD and reduce A\u03b2 uptake and degradation in neurons and astrocytes. Mechanistically, DKKs inhibit A\u03b2 clearance by competitively binding LRP1 and promoting its internalization. In 5\u00d7FAD mice, DKK3 overexpression worsens, while knockout improves, A\u03b2 pathology and cognitive outcomes. A targeted high-throughput screen of ~3000 compounds identified SJ-300 as a potent and selective inhibitor of the DKK3-LRP1 interaction. SJ-300 restores A\u03b2 clearance and rescues cognitive function and neuropathology in 5\u00d7FAD mice. These findings uncover DKK3-LRP1 axis as a contributor for A\u03b2 metabolism and nominate SJ-300 as a promising therapeutic candidate for AD intervention.<\/jats:p>","DOI":"10.1126\/sciadv.adz2099","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T18:58:33Z","timestamp":1762541913000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["DKK3-LRP1 complex and a chemical inhibitor regulate A\u03b2 clearance in models of Alzheimer\u2019s disease"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0635-2894","authenticated-orcid":true,"given":"Ruihan","family":"Yang","sequence":"first","affiliation":[{"name":"Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Psychology, Eastern Illinois University, Charleston, IL 61920, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juxian","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9638-961X","authenticated-orcid":true,"given":"David","family":"Schlessinger","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Genomics, NIA\/NIH-IRP, 251 Bayview Blvd, Room 10B014, Baltimore, MD 21224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4127-1638","authenticated-orcid":true,"given":"Jian","family":"Sima","sequence":"additional","affiliation":[{"name":"Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1197623"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2011.03.003"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40259-023-00633-2"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3233\/ADR-230025"},{"key":"e_1_3_2_6_2","first-page":"605","article-title":"Clearance of Alzheimer\u2019s A\u03b2 peptide: The many roads to perdition","volume":"43","author":"Tanzi R. 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