{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T04:31:30Z","timestamp":1793853090283,"version":"4.6.1"},"reference-count":128,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T00:00:00Z","timestamp":1648684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Since 1995, more than 100 transgenic (Tg) mouse models of Alzheimer\u2019s disease (AD) have been generated in which mutant amyloid precursor protein (APP) or APP\/presenilin 1 (PS1) cDNA is overexpressed (<jats:bold><jats:italic>1st generation models<\/jats:italic><\/jats:bold>). Although many of these models successfully recapitulate major pathological hallmarks of the disease such as amyloid \u03b2 peptide (A\u03b2) deposition and neuroinflammation, they have suffered from artificial phenotypes in the form of overproduced or mislocalized APP\/PS1 and their functional fragments, as well as calpastatin deficiency-induced early lethality, calpain activation, neuronal cell death without tau pathology, endoplasmic reticulum stresses, and inflammasome involvement. Such artifacts bring two important uncertainties into play, these being (1) why the artifacts arise, and (2) how they affect the interpretation of experimental results. In addition, destruction of endogenous gene loci in some Tg lines by transgenes has been reported. To overcome these concerns, single <jats:italic>App<\/jats:italic> knock-in mouse models harboring the Swedish and Beyreuther\/Iberian mutations with or without the Arctic mutation (<jats:italic>App<jats:sup>NL\u2013G\u2013F<\/jats:sup><\/jats:italic> and <jats:italic>App<jats:sup>NL\u2013F<\/jats:sup><\/jats:italic> mice) were developed (<jats:bold><jats:italic>2nd generation models<\/jats:italic><\/jats:bold>). While these models are interesting given that they exhibit A\u03b2 pathology, neuroinflammation, and cognitive impairment in an age-dependent manner, the model with the Artic mutation, which exhibits an extensive pathology as early as 6 months of age, is not suitable for investigating A\u03b2 metabolism and clearance because the A\u03b2 in this model is resistant to proteolytic degradation and is therefore prone to aggregation. Moreover, it cannot be used for preclinical immunotherapy studies owing to the discrete affinity it shows for anti-A\u03b2 antibodies. The weakness of the latter model (without the Arctic mutation) is that the pathology may require up to 18 months before it becomes sufficiently apparent for experimental investigation. Nevertheless, this model was successfully applied to modulating A\u03b2 pathology by genome editing, to revealing the differential roles of neprilysin and insulin-degrading enzyme in A\u03b2 metabolism, and to identifying somatostatin receptor subtypes involved in A\u03b2 degradation by neprilysin. In addition to discussing these issues, we also provide here a technical guide for the application of <jats:italic>App<\/jats:italic> knock-in mice to AD research. Subsequently, a new double knock-in line carrying the <jats:italic>App<jats:sup>NL\u2013F<\/jats:sup><\/jats:italic> and <jats:italic>Psen1<\/jats:italic><jats:sup><jats:italic>P<\/jats:italic>117<jats:italic>L\/WT<\/jats:italic><\/jats:sup> mutations was generated, the pathogenic effect of which was found to be synergistic. A characteristic of this <jats:bold><jats:italic>3rd generation model<\/jats:italic><\/jats:bold> is that it exhibits more cored plaque pathology and neuroinflammation than the <jats:italic>App<jats:sup>NL\u2013G\u2013F<\/jats:sup><\/jats:italic> line, and thus is more suitable for preclinical studies of disease-modifying medications targeting A\u03b2. Furthermore, a derivative <jats:italic>App<jats:sup>G\u2013F<\/jats:sup><\/jats:italic> line devoid of Swedish mutations which can be utilized for preclinical studies of \u03b2-secretase modifier(s) was recently created. In addition, we introduce a new model of cerebral amyloid angiopathy that may be useful for analyzing amyloid-related imaging abnormalities that can be caused by anti-A\u03b2 immunotherapy. Use of the <jats:italic>App<\/jats:italic> knock-in mice also led to identification of the \u03b1-endosulfine-K<jats:sub><jats:italic>ATP<\/jats:italic><\/jats:sub> channel pathway as components of the somatostatin-evoked physiological mechanisms that reduce A\u03b2 deposition <jats:italic>via<\/jats:italic> the activation of neprilysin. Such advances have provided new insights for the prevention and treatment of preclinical AD. Because tau pathology plays an essential role in AD pathogenesis, knock-in mice with human tau wherein the entire murine <jats:italic>Mapt<\/jats:italic> gene has been humanized were generated. Using these mice, the carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) was discovered as a mediator linking tau pathology to neurodegeneration and showed that tau humanization promoted pathological tau propagation. Finally, we describe and discuss the current status of mutant human tau knock-in mice and a non-human primate model of AD that we have successfully created.<\/jats:p>","DOI":"10.3389\/fnins.2022.807473","type":"journal-article","created":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T16:23:34Z","timestamp":1648743814000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":158,"title":["Recent Advances in the Modeling of Alzheimer\u2019s Disease"],"prefix":"10.3389","volume":"16","author":[{"given":"Hiroki","family":"Sasaguri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoko","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Watamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risa","family":"Takamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Nagata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Tsubuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Ohshima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Yoshiki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenya","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wakako","family":"Kumita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinobu","family":"Kitazume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bengt","family":"Winblad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhisa","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaomi C.","family":"Saido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.3233\/jad-210091","article-title":"Neuronal cell cycle re-entry enhances neuropathological features in AppNLF knock-in mice.","volume":"82","author":"Barrett","year":"2021","journal-title":"J. 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