{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:15:17Z","timestamp":1788232517907,"version":"build-2803163510"},"reference-count":63,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tau aggregation plays a critical role in Alzheimer's Disease (AD), where neurofibrillary tangles (NFTs) are a pathological hallmark. While much attention is given to NFTs, emerging evidence highlights nano\u2010sized tau oligomers as toxic entities. Using super\u2010resolution microscopy, we visualized nano\u2010sized tau aggregates (nano\u2010aggregates) in human postmortem brain tissues from intermediate and advanced AD, Primary Age\u2010Related Tauopathy (PART), and controls lacking tau pathology. Surprisingly, tau nano\u2010aggregates hyperphosphorylated at threonine 231 (p\u2010T231) and threonine 181 (p\u2010T181)are detected in control cases, whereas hyperphosphorylated serine 202\/threonine 205 (p\u2010S202\/T205)nano\u2010aggregates are specifically associated with AD and, to a lesser extent, observed in PART. This finding suggests that distinct hyperphosphorylation signatures distinguish physiological from pathological nano\u2010aggregates. Moreover, nano\u2010aggregates exhibit morphological differences between AD and non\u2010AD conditions, increasing in size and complexity in AD. In advanced AD, nano\u2010aggregates typically contain multiple distinct hyperphosphorylated residues, whereas intermediate AD nano\u2010aggregates are predominantly marked by a single hyperphosphorylated residue. These findings reveal novel transitions in the morphology and hyperphosphorylation states of tau nano\u2010aggregates as they shift from physiological to pathological forms. The ability to detect and profile physiological and pathological nanoscale tau aggregates in human brain tissues opens new avenues for studying the molecular underpinnings of tauopathies.<\/jats:p>","DOI":"10.1002\/advs.202509773","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T09:00:14Z","timestamp":1763542814000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Morphological and Hyperphosphorylation Transitions of Nanoscale Tau Aggregates in Alzheimer's Disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Adriana N.","family":"Santiago\u2010Ruiz","sequence":"first","affiliation":[{"name":"Biochemistry, Biophysics, and Chemical Biology Graduate Group University of Pennsylvania  Philadelphia USA"},{"name":"Department of Physiology University of Pennsylvania  Philadelphia 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