RIKEN Says Its Mouse Models Are Now Easier to Obtain
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The Japanese research institute RIKEN has made several mouse models of Alzheimer’s disease more easily accessible. Amyloid precursor protein (APP) mutant knock-ins, APP x MAPT crosses, and mutant presenilin knock-ins are now available as open resources to not-for-profit institutions. RIKEN has simplified the agreements, and it no longer requires RIKEN scientists be listed as co-authors on initial publications that come from use of these animals. Mutant MAPT knock-ins will be made available once details of those mice are published.
For details, see comment from Takaomi Saido below.—Tom Fagan.
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RIKEN Center for Brain Science
RIKEN has now made the App (Saito et al., 2014; Watamura et al., 2022), MAPT crosses (Hashimoto et al., 2019), and Psen1 (Sasaguri et al., 2018) knock-in mice available to nonprofit researchers worldwide as fully open resources with minimal requirements. Mutant MAPT knock-ins (single and multiple) will follow once they are published. All the procedures will be handled at the RIKEN BioResource Center (BRC) home page. Of note, the tedious paperwork that required the providers’ approval has become unnecessary.
The MTA in the past required recipients to acknowledge the providers, according to generally accepted authorship attributions, as co-authors in the first domestic oral presentation, first international oral presentation, and first written international publication as related to the biological resource, unless otherwise requested by the providers. The purpose of co-authorship was not for the providers to increase the number of publications, but rather to confirm compliance with the guidelines on nomenclature, correct use of antibodies, etc., and to discuss the relevance of the observed results in depth.
However, because the number of mutant mouse users has exceeded 600, and because the guidelines are being well accepted, we providers now have decided not to ask for co-authorship anymore unless the recipients desire to do so. All that providers require now is [1] to cite the original paper(s) described in the BRC homepage at the time of publication; [2] to acknowledge the providers.
Please note that the technical issues users need to pay attention to in using the models are described in detail in a review (Sasaguri et al., 2022).
It is also no longer necessary to describe the purpose of using the mice at the time of application. The recipients need to consult the providers when use of the mice has produced intellectual properties.
Please go to the following link to find a list of mutant mice created by the RIKEN Saido laboratory, and to establish a revised MTA with RIKEN BRC: https://knowledge.brc.riken.jp/resource/animal/list?query=saido&__lang__.... (The server appears a bit slow, so please try again if it does not load at first). Scientists who are already using the mice and wish to renew their existing MTAs can do so by contacting RIKEN BRC.
We sincerely hope that our mouse models, which are free of overexpression artifacts, will make additional contributions to the AD research community. I personally recommend use of AppNL-F x Psen1P117L double homozygous mutant mice, because they start accumulating wild-type human Aβ42 at 2 months of age without the interference of the Arctic mutation that would affect metabolism, clearance, and binding of Aβ with such potential binding partners as ApoE (Sasaguri et al, 2022), although making additional crosses would require a lot more time than using the AppNL-G-F mice with the Arctic mutation.
For questions, please contact Dr. Atsushi Yoshiki, Coordinator, RIKEN BRC.
References:
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.
Watamura N, Sato K, Shiihashi G, Iwasaki A, Kamano N, Takahashi M, Sekiguchi M, Mihira N, Fujioka R, Nagata K, Hashimoto S, Saito T, Ohshima T, Saido TC, Sasaguri H. An isogenic panel of App knock-in mouse models: Profiling β-secretase inhibition and endosomal abnormalities. Sci Adv. 2022 Jun 10;8(23):eabm6155. Epub 2022 Jun 8 PubMed.
Hashimoto S, Matsuba Y, Kamano N, Mihira N, Sahara N, Takano J, Muramatsu SI, Saido TC, Saito T. Tau binding protein CAPON induces tau aggregation and neurodegeneration. Nat Commun. 2019 Jun 3;10(1):2394. PubMed.
Sasaguri H, Nagata K, Sekiguchi M, Fujioka R, Matsuba Y, Hashimoto S, Sato K, Kurup D, Yokota T, Saido TC. Introduction of pathogenic mutations into the mouse Psen1 gene by Base Editor and Target-AID. Nat Commun. 2018 Jul 24;9(1):2892. PubMed.
Sasaguri H, Hashimoto S, Watamura N, Sato K, Takamura R, Nagata K, Tsubuki S, Ohshima T, Yoshiki A, Sato K, Kumita W, Sasaki E, Kitazume S, Nilsson P, Winblad B, Saito T, Iwata N, Saido TC. Recent Advances in the Modeling of Alzheimer's Disease. Front Neurosci. 2022;16:807473. Epub 2022 Mar 31 PubMed.
RIKEN Center for Brain Science
Just a note to add. Some scientists want to transfer the mutant mice from another laboratory, rather than RIKEN BRC. This is fine, but I ask them to obtain permission from RIKEN BRC to do so. I also ask them to maintain the genetic background as described by Sasaguri et al., 2022, to avoid accumulation of spontaneous mutations.
References:
Sasaguri H, Hashimoto S, Watamura N, Sato K, Takamura R, Nagata K, Tsubuki S, Ohshima T, Yoshiki A, Sato K, Kumita W, Sasaki E, Kitazume S, Nilsson P, Winblad B, Saito T, Iwata N, Saido TC. Recent Advances in the Modeling of Alzheimer's Disease. Front Neurosci. 2022;16:807473. Epub 2022 Mar 31 PubMed.
UT Southwestern Medical Center at Dallas
APPKI mice (Saito et al., 2014) have been an invaluable resource to our laboratory (Zhang et al., 2015; Ryskamp et al., 2019; Fisher et al., 2016; Zhang et al., 2016), as well as to the AD research community. In these mice, a “humanized” APP gene containing FAD mutations is expressed under the control of endogenous regulatory elements, which enables physiologically relevant modeling of signaling disruptions in AD. For many studies in the field, very aggressive models of amyloid accumulation are used, which may lead to potential artifacts (Sasaguri et al., 2017).
It is a very positive development that APPKI mice are now more easily available for nonprofit research, and hopefully procedures for licensing these mice to the industry are also simplified by RIKEN.
References:
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.
Zhang H, Wu L, Pchitskaya E, Zakharova O, Saito T, Saido T, Bezprozvanny I. Neuronal Store-Operated Calcium Entry and Mushroom Spine Loss in Amyloid Precursor Protein Knock-In Mouse Model of Alzheimer's Disease. J Neurosci. 2015 Sep 30;35(39):13275-86. PubMed.
Ryskamp D, Wu L, Wu J, Kim D, Rammes G, Geva M, Hayden M, Bezprozvanny I. Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor. Neurobiol Dis. 2019 Apr;124:489-504. Epub 2018 Dec 27 PubMed.
Fisher A, Bezprozvanny I, Wu L, Ryskamp DA, Bar-Ner N, Natan N, Brandeis R, Elkon H, Nahum V, Gershonov E, LaFerla FM, Medeiros R. AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer’s Disease. Neurodegener Dis. 2016;16(1-2):95-110. PubMed.
Zhang H, Sun S, Wu L, Pchitskaya E, Zakharova O, Fon Tacer K, Bezprozvanny I. Store-Operated Calcium Channel Complex in Postsynaptic Spines: A New Therapeutic Target for Alzheimer's Disease Treatment. J Neurosci. 2016 Nov 23;36(47):11837-11850. PubMed.
Sasaguri H, Nilsson P, Hashimoto S, Nagata K, Saito T, De Strooper B, Hardy J, Vassar R, Winblad B, Saido TC. APP mouse models for Alzheimer's disease preclinical studies. EMBO J. 2017 Sep 1;36(17):2473-2487. Epub 2017 Aug 1 PubMed.
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