Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jbc.2024.105703

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for the Advancement of Science (AAAS)  

We previously developed single App knock-in mouse models of Alzheimer’s disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation ( App ^NL-G-F and App ^NL-F mice). We have now generated App knock-in mice devoid of the Swedish mutations ( App ^G-F mice) and evaluated its characteristics. Amyloid β peptide (Aβ) pathology was exhibited by App ^G-F mice from 6 to 8 months of age and was accompanied by neuroinflammation. Aβ-secretase inhibitor, verubecestat, attenuated Aβ production in App ^G-F mice, but not in App ^NL-G-F mice, indicating that the App ^G-F mice are more suitable for preclinical studies of β-secretase inhibition given that most patients with AD do not carry the Swedish mutations. Comparison of isogenic App knock-in lines revealed that multiple factors, including elevated C-terminal fragment β (CTF-β) and humanization of Aβ might influence endosomal alterations in vivo. Thus, experimental comparisons between different isogenic App , knock-in mouse lines will provide previously unidentified insights into our understanding of the etiology of AD.

DOI： 10.1126/sciadv.abm6155

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Since 1995, more than 100 transgenic (Tg) mouse models of Alzheimer’s disease (AD) have been generated in which mutant amyloid precursor protein (APP) or APP/presenilin 1 (PS1) cDNA is overexpressed (1st generation models). Although many of these models successfully recapitulate major pathological hallmarks of the disease such as amyloid β peptide (Aβ) 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 App knock-in mouse models harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (App^NL–G–F and App^NL–F mice) were developed (2nd generation models). While these models are interesting given that they exhibit Aβ 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 Aβ metabolism and clearance because the Aβ 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-Aβ 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 Aβ pathology by genome editing, to revealing the differential roles of neprilysin and insulin-degrading enzyme in Aβ metabolism, and to identifying somatostatin receptor subtypes involved in Aβ degradation by neprilysin. In addition to discussing these issues, we also provide here a technical guide for the application of App knock-in mice to AD research. Subsequently, a new double knock-in line carrying the App^NL–F and Psen1^P117L/WT mutations was generated, the pathogenic effect of which was found to be synergistic. A characteristic of this 3rd generation model is that it exhibits more cored plaque pathology and neuroinflammation than the App^NL–G–F line, and thus is more suitable for preclinical studies of disease-modifying medications targeting Aβ. Furthermore, a derivative App^G–F line devoid of Swedish mutations which can be utilized for preclinical studies of β-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-Aβ immunotherapy. Use of the App knock-in mice also led to identification of the α-endosulfine-K_ATP channel pathway as components of the somatostatin-evoked physiological mechanisms that reduce Aβ deposition via 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 Mapt 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.

DOI： 10.3389/fnins.2022.807473

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

We previously developed single App knock-in mouse models of Alzheimer's disease (AD) harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice, respectively). These models showed Aβ pathology, neuroinflammation, and cognitive impairment in an age-dependent manner. The former model exhibits extensive pathology as early as 6 months, but is unsuitable for investigating Aβ metabolism and clearance because the Arctic mutation renders Aβ resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-Aβ antibodies. The latter model may take as long as 18 months for the pathology to become prominent, which leaves an unfulfilled need for an Alzheimer's disease animal model that is both swift to show pathology and useful for antibody therapy. We thus utilized mutant Psen1 knock-in mice into which a pathogenic mutation (P117L) had been introduced to generate a new model that exhibits early deposition of wild-type human Aβ by crossbreeding the AppNL-F line with the Psen1P117L/WT line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new 3rd generation mouse model showed more cored plaque pathology and neuroinflammation than AppNL-G-F mice, and will help accelerate the development of disease-modifying therapies to treat preclinical AD.

DOI： 10.1016/j.jbc.2021.101004

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neulet.2018.01.003

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1073/pnas.1707151114

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.15252/embj.201797397

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00401-016-1554-0

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/hmg/ddt451

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neuroscience.2013.10.055

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1523/JNEUROSCI.4521-09.2010

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Presentation type：Symposium, workshop panel (public)  

Language：English   Presentation type：Symposium, workshop panel (public)  

Language：Japanese   Presentation type：Poster presentation  

Language：English   Presentation type：Symposium, workshop panel (public)  

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Language：Japanese   Presentation type：Oral presentation (general)