{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:39:00Z","timestamp":1790717940429,"version":"4.1.0"},"reference-count":23,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T00:00:00Z","timestamp":1618876800000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:p>Using a new marker of necrosis, pSer46\u2010MARCKS, which was identified by comprehensive phosphoproteome analysis as a phosphoprotein changed before appearance of extracellular amyloid aggregation, we discovered that neuronal necrosis occurs much earlier in Alzheimer's disease pathology than previously expected. The necrosis is induced by intracellular amyloid accumulation that deprives a critical effector molecule, Yes\u2010associated protein (YAP), in the Hippo signaling pathway that is essential for cell survival, similarly to TRIAD necrosis observed in transcriptional repression and in other neurodegenerative diseases such as Huntington's disease. The initial TRIAD necrosis due to the intracellular amyloid releases HMGB1 into extracellular space and induces cluster of secondary necrosis around the primary necrotic neurons. Finally, the cluster grows into extracellular amyloid plaque. Inhibition of HMGB1 by anti\u2010HMGB1 antibody prevents expansion of neurodegeneration. Administration even after onset significantly ameliorates the cognitive decline of Alzheimer's disease model mice. Our results present a new theory of Alzheimer's disease pathology, which can be referred to as the \u201cintracellular amyloid hypothesis\".<\/jats:p>","DOI":"10.1111\/neup.12738","type":"journal-article","created":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T07:34:27Z","timestamp":1618904067000},"page":"93-98","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Intracellular amyloid hypothesis for ultra\u2010early phase pathology of Alzheimer's disease"],"prefix":"10.1111","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6127-5046","authenticated-orcid":false,"given":"Hitoshi","family":"Okazawa","sequence":"first","affiliation":[{"name":"Department of Neuropathology, Center for Brain Integration Research Tokyo Medical and Dental University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,4,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-6147(91)90609-V"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70043-0"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19323"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2017.08.010"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-019-0559-z"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61075-2"},{"key":"e_1_2_10_8_1","unstructured":"Available from URL:https:\/\/investors.biogen.com\/news\u2010releases\/news\u2010release\u2010details\/update\u2010fda\u2010advisory\u2010committees\u2010meeting\u2010aducanumab\u2010alzheimers."},{"key":"e_1_2_10_9_1","unstructured":"Available from URL:https:\/\/news.lilly.co.jp\/down2.php?attach_id=652&category=18&page=1&a.ccess_id=2005"},{"key":"e_1_2_10_10_1","unstructured":"Available from URL:https:\/\/www.alzforum.org\/news\/research\u2010news\/abbvies\u2010tau\u2010antibody\u2010flops\u2010progressive\u2010supranuclear\u2010palsy."},{"key":"e_1_2_10_11_1","unstructured":"Available from URL:https:\/\/www.alzforum.org\/news\/research\u2010news\/gosuranemab\u2010biogens\u2010anti\u2010tau\u2010immunotherapy\u2010does\u2010not\u2010fly\u2010psp."},{"key":"e_1_2_10_12_1","unstructured":"Available from URL:https:\/\/www.nature.com\/articles\/d41573\u2010020\u201000217\u20107."},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1553"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu475"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep31895"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14353-6"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(00)00245-X"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2003.01820.x"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2168"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.08.027"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200509132"},{"key":"e_1_2_10_22_1","first-page":"4749","article-title":"Targeting TEAD\/YAP\u2010transcription\u2010dependent necrosis, TRIAD, ameliorates Huntington's disease pathology","volume":"25","author":"Mao Y","year":"2016","journal-title":"Hum Mol Genet"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.101"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-017-0420-1"}],"container-title":["Neuropathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/neup.12738","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/neup.12738","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/neup.12738","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T20:00:40Z","timestamp":1693598440000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/neup.12738"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4]]},"references-count":23,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,4]]}},"alternative-id":["10.1111\/neup.12738"],"URL":"https:\/\/doi.org\/10.1111\/neup.12738","archive":["Portico"],"relation":{},"ISSN":["0919-6544","1440-1789"],"issn-type":[{"value":"0919-6544","type":"print"},{"value":"1440-1789","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4]]},"assertion":[{"value":"2020-12-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}