{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T16:38:30Z","timestamp":1793291910474,"version":"4.5.0"},"reference-count":52,"publisher":"American Chemical Society (ACS)","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002565","name":"Alzheimer's Drug Discovery Foundation","doi-asserted-by":"publisher","award":["GC-202102-2021435"],"award-info":[{"award-number":["GC-202102-2021435"]}],"id":[{"id":"10.13039\/100002565","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01 AG075084"],"award-info":[{"award-number":["R01 AG075084"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01 AG077672"],"award-info":[{"award-number":["R01 AG077672"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007919","name":"University of Massachusetts","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007919","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The cellular uptake and propagation of tau are central features of tauopathies, including Alzheimer\u2019s disease, and are mediated by the endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1). While prior studies have implicated LRP1 in tau binding and internalization, the biochemical features of this interaction and its suitability for therapeutic targeting remain incompletely defined. Here, we establish a quantitative and scalable framework to interrogate the tau-LRP1 interaction and identify small-molecule modulators. We engineered and purified the LRP1 ligand-binding domain 4 (BD4), a key region mediating tau interaction, and developed multiple orthogonal assays, including fluorescence polarization, split luciferase complementation, and time-resolved FRET, to measure LRP1-BD4 interactions with tau and a known peptide ligand. Across assay formats, we observe consistent binding affinities in the nanomolar range and demonstrate competitive displacement by tau, receptor-associated protein (RAP), and a peptide ligand, supporting overlapping binding interfaces. Leveraging these platforms, we performed small-molecule high-throughput screening and identified a set of candidate inhibitors of the LRP1-BD4-tau interaction. Selected compounds reduced tau uptake in a cellular assay, phenocopying competitive inhibition by tau and a peptide ligand. Together, these studies define the LRP1-BD4-tau interaction as a biochemically tractable and druggable interface and establish an integrated discovery pipeline linking mechanistic characterization to functional cellular outcomes. This work provides a foundation for the development of therapeutic strategies targeting LRP1-mediated tau uptake.<\/jats:p>","DOI":"10.1021\/acschembio.6c00599","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:02:45Z","timestamp":1791903765000},"source":"Crossref","is-referenced-by-count":0,"title":["High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction"],"prefix":"10.1021","author":[{"given":"Caiqin","family":"Wang","sequence":"first","affiliation":[{"name":"University of Massachusetts , , , ,","place":["Amherst, Massachusetts, USA, 01003"]},{"name":"University of Massachusetts , , , ,","place":["Amherst, Massachusetts, USA, 01003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Ting","family":"Ma","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys , , , ,","place":["La Jolla, California, USA, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camryn","family":"Crotty","sequence":"additional","affiliation":[{"name":"University of Massachusetts , , , ,","place":["Amherst, Massachusetts, USA, 01003"]},{"name":"University of Massachusetts , , , ,","place":["Amherst, Massachusetts, USA, 01003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu-Yue","family":"Zeng","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys , , , ,","place":["La Jolla, California, USA, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey","family":"Bobkov","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys , , , ,","place":["La Jolla, California, USA, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Covel","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys , , , ,","place":["La Jolla, California, USA, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica Keane","family":"Rivera","sequence":"additional","affiliation":[{"name":"University of California Santa Barbara , , , ,","place":["Santa Barbara, California, USA, 93106-9010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"Sergienko","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys , , , ,","place":["La Jolla, California, USA, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth S.","family":"Kosik","sequence":"additional","affiliation":[{"name":"University of California Santa Barbara , , , ,","place":["Santa Barbara, California, USA, 93106-9010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven H.","family":"Olson","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys , , , ,","place":["La Jolla, California, USA, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys , , , ,","place":["La Jolla, California, USA, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-5915","authenticated-orcid":true,"given":"Jennifer N.","family":"Rauch","sequence":"additional","affiliation":[{"name":"University of Massachusetts , , , ,","place":["Amherst, Massachusetts, USA, 01003"]},{"name":"University of Massachusetts , , , ,","place":["Amherst, Massachusetts, USA, 01003"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"issue":"6","key":"2026102912075691700_cit1","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/s43587-022-00204-0","article-title":"Biomarker Modeling of Alzheimer\u2019s Disease Using PET-Based Braak Staging","volume":"2","author":"Therriault","year":"2022","journal-title":"Nat Aging"},{"issue":"4","key":"2026102912075691700_cit2","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological Stageing of Alzheimer-Related Changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"issue":"1","key":"2026102912075691700_cit3","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1186\/s40478-017-0488-7","article-title":"What Is the Evidence That Tau Pathology Spreads through Prion-like Propagation?","volume":"5","author":"Mudher","year":"2017","journal-title":"Acta Neuropathol. 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