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We previously showed that amyloid \u03b2 (A\u03b2) toxic conformer with a turn at positions 22\u201323 is essential for forming highly toxic oligomers. In the present study, we evaluated phenotypic changes with aging in AD model AppNL-P-F\/NL-P-F (NL-P-F) mice with Swedish mutation (NL), Iberian mutation (F), and mutation (P) overproducing E22P-A\u03b2, a mimic of toxic conformer utilizing the knock-in technique. Furthermore, the role of the toxic conformer in AD pathology was investigated. NL-P-F mice produced soluble toxic conformers from an early age. They showed impaired synaptic plasticity, glial cell activation, and cognitive decline, followed by the accumulation of A\u03b2 plaques and tau hyperphosphorylation. In addition, the protein expression of hypoxia-inducible factor (HIF)-1\u03b1 was increased, and gene expression of HIF-3\u03b1 was decreased in NL-P-F mice. HIF dysregulation due to the production of soluble toxic conformers may be involved in AD pathology in NL-P-F mice. This study could reveal the role of a highly toxic A\u03b2 on AD pathogenesis, thereby contributing to the development of a novel therapeutic strategy targeting the toxic conformer.<\/jats:p>","DOI":"10.3390\/ijms232113259","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T06:42:17Z","timestamp":1667371337000},"page":"13259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["APP Knock-In Mice Produce E22P-A\u03b2 Exhibiting an Alzheimer\u2019s Disease-like Phenotype with Dysregulation of Hypoxia-Inducible Factor Expression"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5472-4747","authenticated-orcid":false,"given":"Takahito","family":"Maki","sequence":"first","affiliation":[{"name":"Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahito","family":"Sawahata","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ichiro","family":"Akutsu","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shohei","family":"Amaike","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Genki","family":"Hiramatsu","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5644-1348","authenticated-orcid":false,"given":"Daisuke","family":"Uta","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naotaka","family":"Izuo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Therapy and Neuropharmacology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3351-3342","authenticated-orcid":false,"given":"Takahiko","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Aging Stress Response Research Project Team, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7109-8568","authenticated-orcid":false,"given":"Kazuhiro","family":"Irie","sequence":"additional","affiliation":[{"name":"Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University Kitashirakawa-Oiwake-Cho, Kyoto 606-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiaki","family":"Kume","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13024-019-0333-5","article-title":"The neuropathological diagnosis of Alzheimer\u2019s disease","volume":"14","author":"DeTure","year":"2019","journal-title":"Mol. 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