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All these p-tau proteins are detected in neurofibrillary tangles in brains obtained post-mortem from Alzheimer\u2019s disease patients. However, increases in p-tau levels in cerebrospinal fluid and plasma during the preclinical stage of Alzheimer\u2019s disease correlate with amyloid-\u03b2 burden and precede neurofibrillary tangles in brains, suggesting that these p-tau proteins are indicative of amyloid-\u03b2-mediated brain pathology. In addition, phospho-tau 217 has greater sensitivity than phospho-tau 181, though it is unclear whether each of these p-tau variants contributes to the same or a different type of neuropathology prior to neurofibrillary tangle formation. In this study, we evaluated the intracerebral localization of p-tau in App knock-in mice with amyloid-\u03b2 plaques without neurofibrillary tangle pathology (AppNLGF), in App knock-in mice with increased amyloid-\u03b2 levels without amyloid-\u03b2 plaques (AppNL) and in wild-type mice. Immunohistochemical analysis showed that phospho-tau 217 and phospho-tau 231 were detected only in AppNLGF mice as punctate structures around amyloid-\u03b2 plaques, overlapping with the tau pathology marker, AT8 epitope phospho-tau 202\/205\/208. Moreover, phospho-tau 217 and phospho-tau 202\/205\/208 colocalized with the postsynaptic marker PSD95 and with a major tau kinase active, GSK3\u03b2. In contrast and similar to total tau, phospho-tau 181 signals were readily detectable as fibre structures in wild-type and AppNL mice and colocalized with an axonal marker neurofilament light chain. In AppNLGF mice, these phospho-tau 181-positive structures were disrupted around amyloid-\u03b2 plaques and only partially overlapped with phospho-tau 217. These results indicate that phospho-tau 217, phospho-tau 231 and a part of phospho-tau 181 signals are markers of postsynaptic pathology around amyloid-\u03b2 plaques, with phospho-tau 181 also being a marker of axonal abnormality caused by amyloid-\u03b2 burden in brains.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac286","type":"journal-article","created":{"date-parts":[[2022,11,6]],"date-time":"2022-11-06T15:09:00Z","timestamp":1667747340000},"source":"Crossref","is-referenced-by-count":38,"title":["Distinct brain pathologies associated with Alzheimer\u2019s disease biomarker-related phospho-tau 181 and phospho-tau 217 in <i>App<\/i> knock-in mouse models of amyloid-\u03b2 amyloidosis"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7107-2197","authenticated-orcid":false,"given":"Yu","family":"Hirota","sequence":"first","affiliation":[{"name":"Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology , Obu, Aichi 474-8511 , Japan"},{"name":"Research Fellow of Japan Society for the Promotion of Science , Chiyoda-ku, Tokyo 102-0083 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasufumi","family":"Sakakibara","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology , Obu, Aichi 474-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Ibaraki","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology , Obu, Aichi 474-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimi","family":"Takei","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology , Obu, Aichi 474-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi M","family":"Iijima","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology , Obu, Aichi 474-8511 , Japan"},{"name":"Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University , Nagoya 467-8603 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8275-8293","authenticated-orcid":false,"given":"Michiko","family":"Sekiya","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology , Obu, Aichi 474-8511 , Japan"},{"name":"Department of Experimental Gerontology, Graduate School of 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