{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:05:24Z","timestamp":1789653924859,"version":"4.0.0"},"reference-count":224,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is the leading cause of dementia in the elderly, pathologically defined by extracellular amyloid-\u03b2 plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. The Braak staging system established that tau pathology spreads in a stereotypical pattern across the brain, supporting the \u201cprion-like\u201d hypothesis: misfolded tau aggregates serve as seeds, inducing the misfolding and aggregation of normal tau, and thereby driving disease progression along neuroanatomical pathways. In the past 5 years (2021\u20132026), substantial advances have elucidated the molecular mechanisms underlying tau seeding activity. This review summarizes recent progress in tau seeding research, highlighting both intrinsic and extrinsic regulators of tau prion-like activity. Intrinsic factors include the structural basis of tau strains, MAPT mutations, alternative splicing (3R\/4R isoforms), post-translational modifications, and liquid\u2013liquid phase separation. Extrinsic factors encompass cofactors, molecular chaperones, non-coding RNAs, epigenetic mechanisms, environmental exposures, and the emerging concept of trans-seeding by heterologous protein fibrils. We also review therapeutic strategies targeting tau pathology, focusing on their mechanisms and clinical development. Integrating these mechanistic insights and therapeutic advances will inform future research and clinical strategies for AD and related tauopathies.<\/jats:p>","DOI":"10.3389\/fnins.2026.1927017","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T13:41:46Z","timestamp":1789652506000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"20","author":[{"given":"Jin","family":"Miao","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine (Institute of Comparative Medicine), Yangzhou University, Yangzhou","place":["Jiangsu, China"]},{"name":"Laboratory Animal Center, Nantong University, Nantong","place":["Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhong","family":"Xue","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong","place":["Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuchao","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong","place":["Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlan","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong","place":["Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Chu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong","place":["Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaichang","family":"Sun","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine (Institute of Comparative Medicine), Yangzhou University, Yangzhou","place":["Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3312","DOI":"10.1038\/s41467-025-58585-w","article-title":"GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau.","volume":"16","author":"Acosta Ingram","year":"2025","journal-title":"Nat. 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