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We developed a highly sensitive and selective ELISA for high\u2010molecular\u2010weight oligomer tau (HMWoTau) with LLOQ of 0.3\u2009pg\/well for the first time, using a novel mouse monoclonal antibody APNmAb005. The target molecule was identified as HMWoTau with circa 2000 kD as a minimum size and the more oligomerized species (&gt;5000 kD), in combination analysis with Size\u2010Exclusion\u2010Chromatography and Sucrose\u2010Density\u2010Gradient\u2010Centrifugation for both recombinant human (rh) Tau\u2010derived aggregates and AD brain\u2010lysates in PBS(\u2212). HMWoTau was labeled by Thioflavin S and visualized as a homogeneous globular particle (about 30\u2009nm in diameter) by two different technologies of atomic force microscopy and dSTORM\u2010Nanoimager. Specific quantitation was also confirmed by immune\u2010absorption, rhHMWoTau\u2010spiked, and cross\u2010reactivity studies. APNmAb005 failed to detect the HMWoTau signal by treatment with DTT\/SDS under no influence on the pan\u2010tau antibody, indicating its conformation\u2010specific recognition. APNmAb005\u2010ELISA showed AD\u2010specific and statistically significant ELISA signals from 1\u2009ng brain lysate protein\/well. Analysis of the frontal neocortex (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200940, Braak stage I\u2013VI) by ELISA revealed the detection\u2010limit levels of HMWoTau species at stage I\u2013III, and drastic and statistically significant increases at stage V\/VI (AD). By contrast, total Tau and p181 Tau showed 1\/4\u20131\/5 levels of AD even at Stage I, while both tau species also showed a statistically significant increase in AD. In sum, our novel APNmAb005\u2010ELISA clarified the disease\u2010specific increase in HMWoTau species and will be useful for not only further etiological elucidation but also the potential diagnostics in AD and relevant tauopathy.\n                  <\/jats:p>","DOI":"10.1096\/fj.202401704r","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T11:50:04Z","timestamp":1732103404000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["High\u2010molecular\u2010weight oligomer tau (\n                    <scp>HMWoTau<\/scp>\n                    ) species are dramatically increased in Braak\u2010stage dependent manner in the frontal lobe of human brains, demonstrated by a novel oligomer Tau\n                    <scp>ELISA<\/scp>\n                    with a mouse monoclonal antibody (\n                    <scp>APNmAb005<\/scp>\n                    )"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2489-9121","authenticated-orcid":false,"given":"Hiroaki","family":"Fukumoto","sequence":"first","affiliation":[{"name":"Department of Preclinical Research Division APRINOIA Therapeutics Inc.  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