Faculty Profiles - NAGATA Kenichi

Papers - NAGATA Kenichi

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Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice Reviewed

Kenichi Nagata, Shoko Hashimoto, Daisuke Joho, Ryo Fujioka, Yukio Matsuba, Misaki Sekiguchi, Naomi Mihira, Daisuke Motooka, Yu-Chen Liu, Daisuke Okuzaki, Masataka Kikuchi, Shigeo Murayama, Takaomi C. Saido, Hiroshi Kiyama, Hiroki Sasaguri

eNeuro page： ENEURO.0260 - 24.2024 2024.11

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

Unique microglial states have been identified in Alzheimer’s disease (AD) model mice and postmortem AD brains. Although it has been well documented that amyloid-β accumulation induces the alteration of microglial states, the relationship between tau pathology and microglial states remains incompletely understood because of a lack of suitable AD models. In the present study, we generated a novel AD model mouse by the intracerebral administration of tau purified from human brains with primary age-related tauopathy intoAppknock-in mice with humanized tau. Immunohistochemical analyses revealed that Dectin-1-positive disease-associated microglia were increased in the AD model mice after tau accumulation in the brain. We then performed single-nucleus RNA sequencing on the AD model mice to evaluate the differences in microglial states with and without tau propagation and accumulation. By taking advantage of spatial transcriptomics and existing single-cell RNA sequencing datasets, we showed for the first time that tau propagation and accumulation induce a disease-associated microglial phenotype at the expense of an age-related non-homeostatic counterpart (namely, white matter-associated microglia) in an AD model mouse brain. Future work using spatial transcriptomics at single-cell resolution will pave the way for a more appropriate interpretation of microglial alterations in response to tau pathology in the AD brain.

Significance StatementWe generated a novel Alzheimer's disease model mouse showing humanized tau accumulation and propagation after amyloid beta accumulation. Immunohistochemical analyses revealed that disease-associated microglia were increased in the model mice after tau accumulation in the brain. Using single-cell RNA-seq and spatial transcriptomics, we showed for the first time that tau propagation and accumulation induce a disease-associated microglial phenotype at the expense of an age-related non-homeostatic counterpart in the model mouse brain.

DOI： 10.1523/eneuro.0260-24.2024

Introduction of pathogenic mutations into the mouse Psen1 gene by Base Editor and Target-AID Reviewed

Sasaguri H, Nagata K, c, Sekiguchi M, Fujioka R, Matsuba Y, Hashimoto S, Sato K, Kurup D, Yokota T, Saido TC

Nat Commun. Vol. 9 ( 1 ) page： 2892 2018.7

Generation of App knock-in mice reveals deletion mutations protective against Alzheimer’s disease-like pathology Reviewed

Kenichi Nagata, Mika Takahashi, Yukio Matsuba, Fumi Okuyama-Uchimura, Kaori Sato, Shoko Hashimoto, Takashi Saito, Takaomi C. Saido

Nature Communications Vol. 9 ( 1 ) page： 1800 2018.5

Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders Reviewed

Kenichi Nagata, Mika Takahashi, Sumiko Kiryu-Seo, Hiroshi Kiyama, Takaomi C. Saido

ACTA NEUROPATHOLOGICA COMMUNICATIONS Vol. 5 ( 83 ) 2017.11

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

Endothelin-converting enzyme-like 1 (ECEL1, also termed DINE in rodents), a membrane-bound metalloprotease, has been identified as a gene responsible for distal arthrogryposis (DA). ECEL1-mutated DA is generally characterized by ocular phenotypes in addition to the congenital limb contractures that are common to all DA subtypes. Until now, the consequences of the identified pathogenic mutations have remained incompletely understood because of a lack of detailed phenotypic analyses in relevant mouse models. In this study, we generated a new knock-in mouse strain that carries an ECEL1/DINE pathogenic G607S missense mutation, based on a previous study reporting atypical DA hindlimb phenotypes in two siblings with the mutation. We compared the morphological phenotypes of G607S knock-in mice with C760R knock-in mice that we previously established. Both C760R and G607S knock-in mouse embryos showed similar axonal arborization defects with normal trajectory patterns from the spinal cord to the target hindlimb muscles, as well as axon guidance defects of the abducens nerves. Intriguingly, distinct phenotypes in DINE protein localization and mRNA expression were identified in these knock-in mouse lines. For G607S, DINE mRNA and protein expression was decreased or almost absent in motor neurons. In the C760R mutant mice DINE was expressed and localized in the somata of motor neurons but not in axons. Our mutant mouse data suggest that ECEL1/DINE G607S and C760R mutations both lead to motor innervation defects as primary causes in ECEL1-mutated congenital contracture disorders. However, the functional consequences of the two mutations are distinct, with loss of axonal transport of ECEL1/DINE in C760R mutants and mRNA expression deficits in G607S mutants.

DOI： 10.1186/s40478-017-0486-9

Web of Science

Rod-shaped microglia represent a morphologically distinct subpopulation of disease-associated microglia Reviewed

Yukio Matsuba, Kenichi Nagata, Yosuke Kadota, Naruhiko Sahara, Takaomi C. Saido, Shoko Hashimoto

Journal of Neuroinflammation Vol. 22 ( 1 ) 2025.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Microglia, resident immune cells of the central nervous system, play an essential role in responding to pathological conditions by adopting diverse activation states and morphologies. Recent single-cell RNA sequencing have revealed that microglial subtypes were heterogeneous based on their gene expression profiles. However, the mechanism on how morphological changes in microglia are correlated with their gene expression profiles remains unclear. The current study aimed to identify a distinct population of rod-shaped microglia, characterized by an elongated morphology, in glutamyl cysteine ligase (GCLC)-deficient mice, a model of glutathione deficiency-induced oxidative stress. In the process of brain atrophy accompanied by neuronal cell death, which was observed in GCLC-KO mice, the rod-shaped microglia emerged in early stages of neurodegeneration and subsequently decreased in number over time. C1q-mediated synaptic pruning has been implicated in microglial activation under pathological conditions. Thus, whether C1q contributes to the formation of rod-shaped microglia was investigated. Notably, the genetic deletion of C1q did not affect the number or distribution of rod-shaped microglia in GCLC-KO mice. These findings suggest that their formation occurs via a C1q-independent mechanism. According to morphological and molecular analyses, the gene expression profile of the rod-shaped microglia was similar to that of the disease-associated microglia (DAM). To investigate the mechanisms underlying their formation, single-nucleus RNA sequencing was performed on cortical tissues collected from GCLC-KO mice. DAM-like microglial clusters were consistently identified. Further, pathway enrichment analysis suggested the potential involvement of the urokinase-type plasminogen activator (uPA, encoded by Plau) signaling. Considering the role of uPA in extracellular matrix degradation and cell migration, it may contribute to the morphological changes in rod-shaped microglia. In addition, the phosphorylation of growth-associated protein 43 (GAP43), a modification linked to structural plasticity, increased in rod-shaped microglia. Based on these findings, uPA signaling and phosphorylated GAP43 may be involved in microglial elongation and alignment along neuronal fibers, which potentially facilitate their migration during early neurodegenerative responses. Taken together, the rod-shaped microglia are a previously unrecognized activated population that emerges early in neurodegeneration and may be involved in disease-related processes. Understanding their molecular regulation can provide insights into early microglial responses and potential therapeutic targets.

DOI： 10.1186/s12974-025-03504-5

Other Link： https://link.springer.com/article/10.1186/s12974-025-03504-5/fulltext.html

Production of a heterozygous exon skipping model of common marmosets using gene-editing technology Reviewed

Kenya Sato, Hiroki Sasaguri, Wakako Kumita, Tetsushi Sakuma, Tomoe Morioka, Kenichi Nagata, Takashi Inoue, Yoko Kurotaki, Naomi Mihira, Michihira Tagami, Ri-ichiroh Manabe, Kokoro Ozaki, Yasushi Okazaki, Takashi Yamamoto, Makoto Suematsu, Takaomi C. Saido, Erika Sasaki

Lab Animal Vol. 53 ( 9 ) page： 244 - 251 2024.8

Gene-gene functional relationships in Alzheimer’s disease: CELF1 regulates KLC1 alternative splicing Reviewed

Masataka Kikuchi, Justine Viet, Kenichi Nagata, Masahiro Sato, Geraldine David, Audic Yann, Michael A. Silverman, Mitsuko Yamamoto, Hiroyasu Akatsu, Yoshio Hashizume, Shuko Takeda, Shoshin Akamine, Tesshin Miyamoto, Ryota Uozumi, Shiho Gotoh, Kohji Mori, Manabu Ikeda, Luc Paillard, Takashi Morihara

Biochemical and Biophysical Research Communications page： 150025 - 150025 2024.4

eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS Reviewed

Shiho Gotoh, Kohji Mori, Yuzo Fujino, Yuya Kawabe, Tomoko Yamashita, Tsubasa Omi, Kenichi Nagata, Shinji Tagami, Yoshitaka Nagai, Manabu Ikeda

Journal of Biological Chemistry Vol. 300 ( 3 ) page： 105703 - 105703 2024.3

An isogenic panel of App knock-in mouse models: Profiling β-secretase inhibition and endosomal abnormalities Reviewed

Naoto Watamura, Kaori Sato, Gen Shiihashi, Ayami Iwasaki, Naoko Kamano, Mika Takahashi, Misaki Sekiguchi, Naomi Mihira, Ryo Fujioka, Kenichi Nagata, Shoko Hashimoto, Takashi Saito, Toshio Ohshima, Takaomi C. Saido, Hiroki Sasaguri

Science Advances Vol. 8 ( 23 ) 2022.6

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

Recent Advances in the Modeling of Alzheimer’s Disease International journal

Hiroki Sasaguri, Shoko Hashimoto, Naoto Watamura, Kaori Sato, Risa Takamura, Kenichi Nagata, Satoshi Tsubuki, Toshio Ohshima, Atsushi Yoshiki, Kenya Sato, Wakako Kumita, Erika Sasaki, Shinobu Kitazume, Per Nilsson, Bengt Winblad, Takashi Saito, Nobuhisa Iwata, Takaomi C. Saido

Frontiers in Neuroscience Vol. 16 page： 807473 - 807473 2022.3

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 (AppNL–G–F and AppNL–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 AppNL–F and Psen1P117L/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 AppNL–G–F line, and thus is more suitable for preclinical studies of disease-modifying medications targeting Aβ. Furthermore, a derivative AppG–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-KATP 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

A 3rd generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide. International journal

Kaori Sato, Naoto Watamura, Ryo Fujioka, Naomi Mihira, Misaki Sekiguchi, Kenichi Nagata, Toshio Ohshima, Takashi Saito, Takaomi C Saido, Hiroki Sasaguri

The Journal of biological chemistry page： 101004 - 101004 2021.7

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

Biology of splicing in Alzheimer's disease research. Invited Reviewed

Nagata K, Saito T, Saido TC, Morihara T

Prog Mol Biol Transl Sci. Vol. 168 page： 79 - 84 2019.10

New Insights of a Neuronal Peptidase DINE/ECEL1: Nerve Development, Nerve Regeneration and Neurogenic Pathogenesis. Invited Reviewed

Kiryu-Seo S, Nagata K, Saido TC, Kiyama H

Neurochem Res. 2018.10

Methylation changes and aberrant expression of FGFR3 in Lewy body disease neurons. Reviewed

Tsuchida T, Mano T, Kagari Koshi-Mano, Bannai T, Matsubara T, Yamashita S, Ushijima T, Nagata K, Murayama S, Toda T, Tsuji S, Iwata A

Brain Res 2018.6

DNA methylation level of the neprilysin promoter in Alzheimer's disease brains. Reviewed

Nagata K, Mano T, Murayama S, Saido TC, Iwata A

Neurosci Lett. Vol. 670 page： 8 - 13 2018.3

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease Reviewed

Mano T, Nagata K, Nonaka T, Tarutani A, Imamura T, Hashimoto T, Bannai T, Koshi-Mano K, Tsuchida T, Ohtomo R, Takahashi-Fujigasaki J, Yamashita S, Ohyagi Y, Yamasaki R, Tsuji S, Tamaoka A, Ikeuchi T, Saido TC, Iwatsubo T, Ushijima T, Murayama S, Hasegawa M, Iwata A

Proc Natl Acad Sci U S A 2017.11

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease. Reviewed

Proc Natl Acad Sci U S A 2017.10

APP mouse models for Alzheimer's disease preclinical studies. Reviewed

Sasaguri H, Nilsson P, Hashimoto S, Nagata K, Saito T, De Strooper B, Hardy J, Vassar R, Winblad B, Saido TC

EMBO J Vol. 36 ( 17 ) page： 2473 - 2487 2017.9

ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis Reviewed

Nagata K*(co-corresponding), Kiryu-Seo S, Tamada H, Okuyama-Uchimura F, Kiyama H*, Saido TC*

Acta Neuropathologica 2016.7

Altered CpG methylation in sporadic Alzheimer's disease is associated with APP and MAPT dysregulation Reviewed

Iwata A, Nagata K, Hatsuta H, Takuma H, Bundo M, Iwamoto K, Tamaoka A, Murayama S, Saido T, Tsuji S

Human Molecular Genetics 2014.2

microRNA-124 is down regulated in nerve-injured motor neurons and it potentially targets mRNAs for KLF6 and STAT3 Reviewed

Nagata K# (contributed equally), Hama I#, Kiryu-Seo S, Kiyama H

Neuroscience 2014.1

Damage-induced neuronal endopeptidase is critical for presynaptic formation of neuromuscular junctions Reviewed

Nagata K, Kiryu-Seo S, Maeda M, Yoshida K, Morita T, Kiyama H

Journal of Neuroscience 2010.5

Localization and ontogeny of damage-induced neuronal endopeptidase mRNA-expressing neurons in the rat nervous system Reviewed

Nagata K, Kiryu-Seo S, Kiyama H

Neuroscience Vol. 141 ( 1 ) page： 299-310 2006.8

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Papers - NAGATA Kenichi