{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T18:54:29Z","timestamp":1773860069265,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2015,12,2]],"date-time":"2015-12-02T00:00:00Z","timestamp":1449014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009947","name":"Merck Sharp and Dohme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009947","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Neurofibrillary tangles (NFTs), a cardinal pathological feature of neurodegenerative disorders, such as Alzheimer's disease (AD) are primarily composed of hyper\u2010phosphorylated tau protein. Recently, several other molecules, including flotillin\u20101, phosphatidylinositol\u20104,5\u2010bisphosphate [PtdIns(4,5)P2] and cyclin\u2010dependent kinase 5 (CDK5), have also been revealed as constituents of NFTs. Flotillin\u20101 and PtdIns(4,5)P2 are considered markers of raft microdomains, whereas CDK5 is a tau kinase. Therefore, we hypothesized that NFTs have a relationship with raft domains and the tau phosphorylation that occurs within NFTs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated six cases of AD, six cases of other neurodegenerative diseases with NFTs and three control cases. We analysed the PtdIns(4,5)P2\u2010immunopositive material in detail, using super\u2010resolution microscopy and electron microscopy to elucidate its pattern of expression. We also investigated the spatial relationship between the PtdIns(4,5)P2\u2010immunopositive material and tau kinases through double immunofluorescence analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2\u2010immunopositive small vesicles (approximately 1 <jats:italic>\u03bc<\/jats:italic>m in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons. These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase\u20103<jats:italic>\u03b2<\/jats:italic> and spleen tyrosine kinase.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These observations suggest that clusters of raft\u2010derived vesicles that resemble GVD bodies are substructures of pretangles other than PHFs. These tau kinase\u2010bearing vesicles are likely involved in the modification of tau protein and in NFT formation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12288","type":"journal-article","created":{"date-parts":[[2015,10,26]],"date-time":"2015-10-26T14:20:51Z","timestamp":1445869251000},"page":"639-653","source":"Crossref","is-referenced-by-count":22,"title":["The identification of raft\u2010derived tau\u2010associated vesicles that are incorporated into immature tangles and paired helical filaments"],"prefix":"10.1111","volume":"42","author":[{"given":"T.","family":"Nishikawa","sequence":"first","affiliation":[{"name":"Department of Clinical Neuroscience and Therapeutics Hiroshima University Graduate School of Biomedical and Health Sciences Hiroshima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience and Therapeutics Hiroshima University Graduate School 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