{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T13:23:17Z","timestamp":1787404997764,"version":"build-2736575974"},"reference-count":49,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22237003"],"award-info":[{"award-number":["22237003"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["92353302"],"award-info":[{"award-number":["92353302"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2022LSW014"],"award-info":[{"award-number":["ZR2022LSW014"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tau aggregation and hyperphosphorylation are key pathological features of Alzheimer\u2019s disease (AD). Because Tau is intrinsically disordered, conventional small-molecule inhibitors have achieved limited success. Proteolysis-targeting chimeras (PROTACs) enable the targeted proteasomal degradation of previously considered undruggable proteins. We designed Tau-targeted PROTAC candidates using methylene blue (MB) as a recognition moiety for aggregation-prone motifs within the microtubule-binding region and varied the linker lengths and E3 ligase recruitment ligands to optimize degradation efficiency. Cell-based screening revealed that MB-2-VHL1 and MB-2-VHL2 are active degraders. In vivo studies confirmed a reduction in total Tau levels and degradation of phosphorylated Tau (p-Tau). In 3xTg-AD mice, subcutaneous administration of MB-2-VHL2 was associated with reduced hippocampal Tau and p-Tau levels and improved recognition memory and spatial learning. MB-2-VHL2 was also detectable in both serum and brain tissue by LC\u2013MS\/MS after subcutaneous administration and did not cause detectable histological or biochemical toxicity. These results indicate that MB-2-VHL2 can reduce both total Tau and p-Tau levels in vivo. Although the reduction in p-Tau appeared more pronounced under our experimental conditions, whether MB-2-VHL2 preferentially targets pathological Tau remains to be determined. Overall, these findings support further optimization and preclinical evaluation of Tau-targeted PROTACs as a potential therapeutic strategy for AD.<\/jats:p>","DOI":"10.1021\/acschembio.6c00096","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:13:02Z","timestamp":1785849182000},"page":"1906-1916","source":"Crossref","is-referenced-by-count":0,"title":["Tau-Targeted\nPROTACs Degrade Pathology-Associated\nTau and Improve Memory in Alzheimer\u2019s Disease Models"],"prefix":"10.1021","volume":"21","author":[{"given":"Tian","family":"Zhao","sequence":"first","affiliation":[{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Sen","family":"Wang","sequence":"additional","affiliation":[{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2640-7170","authenticated-orcid":true,"given":"Yeh-Jun","family":"Lim","sequence":"additional","affiliation":[{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Central South University , , ,","place":["Changsha, China, 410008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Rong","family":"Duan","sequence":"additional","affiliation":[{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Li","sequence":"additional","affiliation":[{"name":"Qilu Pharmaceutical Co., Ltd , , ,","place":["Jinan, Shandong, China, 250101"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1215-5010","authenticated-orcid":true,"given":"Yan-Mei","family":"Li","sequence":"additional","affiliation":[{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]},{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"issue":"6","key":"2026082208553695400_cit1","doi-asserted-by":"publisher","first-page":"590","DOI":"10.3390\/brainsci14060590","article-title":"Research Progress on the Pathogenesis, Diagnosis, and Drug Therapy\nof Alzheimer\u2019s Disease","volume":"14","author":"Yang","year":"2024","journal-title":"Brain Sci."},{"key":"2026082208553695400_cit2","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1146\/annurev.pathol.1.110304.100113","article-title":"Neurodegenerative\ndiseases: new concepts\nof pathogenesis and their therapeutic implications","volume":"1","author":"Skovronsky","year":"2006","journal-title":"Annu. Rev. Pathol."},{"issue":"8059","key":"2026082208553695400_cit3","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1038\/d41586-025-01101-3","article-title":"Alzheimer\u2019s\ndisease: highlights from research","volume":"640","author":"Drew","year":"2025","journal-title":"Nature"},{"issue":"1","key":"2026082208553695400_cit4","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s00401-024-02751-9","article-title":"Brain vasculature\naccumulates tau and is spatially related to tau tangle pathology in\nAlzheimer\u2019s disease","volume":"147","author":"Hoglund","year":"2024","journal-title":"Acta Neuropathol."},{"key":"2026082208553695400_cit5","doi-asserted-by":"publisher","first-page":"109030","DOI":"10.1016\/j.bioorg.2025.109030","article-title":"Aggregation\ninhibitors of tau protein with anti-inflammatory potential against\nneurodegeneration","volume":"165","author":"Nehmeh","year":"2025","journal-title":"Bioorg. 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Graphics Modell."},{"issue":"1","key":"2026082208553695400_cit25","doi-asserted-by":"publisher","first-page":"2677","DOI":"10.1038\/s41467-024-46898-1","article-title":"Phosphorylation and O-GlcNAcylation at the same \u03b1-synuclein\nsite generate distinct fibril structures","volume":"15","author":"Hu","year":"2024","journal-title":"Nat.\nCommun."},{"key":"2026082208553695400_cit26","doi-asserted-by":"publisher","first-page":"100235","DOI":"10.1016\/j.slasd.2025.100235","article-title":"Hyperphosphorylated tau-based Alzheimer\u2019s Disease\ndrug discovery: Identification of inhibitors of tau aggregation and\ncytotoxicity","volume":"33","author":"Hagar","year":"2025","journal-title":"SLAS Discovery"},{"key":"2026082208553695400_cit27","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.actbio.2024.06.001","article-title":"Carbon dots as dual\ninhibitors of tau and amyloid-beta aggregation\nfor the treatment of Alzheimer\u2019s disease","volume":"183","author":"Zhang","year":"2024","journal-title":"Acta Biomater."},{"issue":"3","key":"2026082208553695400_cit28","doi-asserted-by":"publisher","first-page":"999","DOI":"10.3233\/JAD-170351","article-title":"Curcumin Inhibits Tau\nAggregation\nand Disintegrates Preformed Tau Filaments in vitro","volume":"60","author":"Rane","year":"2017","journal-title":"J. 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Am. Chem.\nSoc."},{"issue":"11","key":"2026082208553695400_cit33","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.3390\/cancers17111871","article-title":"Targeting the Undruggable: Recent Progress in PROTAC-Induced Transcription\nFactor Degradation","volume":"17","author":"Jung","year":"2025","journal-title":"Cancers"},{"issue":"1","key":"2026082208553695400_cit34","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/s41419-025-07535-x","article-title":"Decoy-PROTAC for specific degradation of \u201cUndruggable\u201d\nSTAT3 transcription factor","volume":"16","author":"Li","year":"2025","journal-title":"Cell Death Dis."},{"issue":"1","key":"2026082208553695400_cit35","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/s12943-024-02024-9","article-title":"New-generation\nadvanced PROTACs as potential therapeutic agents in cancer therapy","volume":"23","author":"Wang","year":"2024","journal-title":"Mol. 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Soc."},{"key":"2026082208553695400_cit47","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1039\/B403615H","article-title":"Effective stabilisation\nof alpha-helical structures in short peptides with acetylenic cross-linking\nagents","volume":"11","author":"Fujimoto","year":"2004","journal-title":"Chem. Commun."},{"key":"2026082208553695400_cit48","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.bioorg.2018.11.042","article-title":"TDP-43 specific\nreduction induced by Di-hydrophobic tags conjugated peptides","volume":"84","author":"Gao","year":"2019","journal-title":"Bioorg. Chem."},{"issue":"1","key":"2026082208553695400_cit49","doi-asserted-by":"publisher","first-page":"8857","DOI":"10.1038\/s41467-025-63928-8","article-title":"Discovery\nof a CNS active GSK3 degrader using orthogonally\nreactive linker screening","volume":"16","author":"Holmqvist","year":"2025","journal-title":"Nat. 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