{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:34:03Z","timestamp":1787027643916,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Teikyo University"},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K06498"],"award-info":[{"award-number":["21K06498"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K07503"],"award-info":[{"award-number":["22K07503"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The aggregation of tau protein is a central pathological event in Alzheimer\u2019s disease, and this pathology is hypothesized to spread via a prion-like mechanism driven by tau \u201cseeds\u201d. While aggregated tau from Alzheimer\u2019s disease brains is known to contain age-related d-isomerized aspartic acid (d-Asp) residues, it remains unknown how this modification affects the seeding activity that drives disease propagation. Here, we investigated the impact of site-specific d-isomerization within R2 and R3 tau repeat-domain peptides, which form the core of tau fibrils. We demonstrate that the stereochemical integrity of these peptides is critical for their seeding function. d-isomerization at Asp314 within the R3 peptide seed severely impaired its ability to template the fibrillization of full-length tau in vitro. This finding was validated in a cellular model, where R3 seeds containing d-Asp314 were significantly less potent at inducing the formation of phosphorylated tau aggregates compared to wild-type seeds. Our results establish that Asp d-isomerization within tau seeds acts as a potent attenuator of their pathological seeding activity, suggesting this spontaneous modification may intrinsically modulate the progression of Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/biom16010143","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T11:42:58Z","timestamp":1768304578000},"page":"143","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Site-Specific Aspartic Acid d-Isomerization in Tau R2 and R3 Peptide Seeds Attenuates Seed-Induced Fibril Formation of Full-Length Tau"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6370-1099","authenticated-orcid":false,"given":"Genta","family":"Ito","sequence":"first","affiliation":[{"name":"Department of Biomolecular Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo 173-8605, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo 173-8605, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Isoo","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Teikyo University, Tokyo 173-8605, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4362-7439","authenticated-orcid":false,"given":"Toshihiro","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Teikyo University, Tokyo 173-8605, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Utsunomiya-Tate","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo 173-8605, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13024-019-0333-5","article-title":"The Neuropathological Diagnosis of Alzheimer\u2019s Disease","volume":"14","author":"DeTure","year":"2019","journal-title":"Mol. 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