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Section of Genetics and Pathobiology

Our mission

The goals of our research are to elucidate molecular mechanisms underlying the pathogenesis of Alzheimer's disease (AD) and to identify novel risk factors and therapeutic targets for AD.



   Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of the senile dementia. Accumulation of amyloid-β peptides (Aβ) in the brains is believed to initiate decades-long AD pathogenesis. From the results of recent clinical trials for amyloid-targeting therapy, we learned that, in order to halt disease progression of AD, it is crucial to target neurodegenerative process downstream of Aβ accumulation. However, there is no such therapy to date, and molecular mechanisms underlying AD pathogenesis still remain largely unknown. Through integration of genetic and transcriptome data from AD brains, network analysis in systems biology, and experimental validation using latest animal models, our laboratory is trying to decipher complex AD pathogenesis at cellular and gene network levels (Figure 1). The goal of our study is to identify "gene regulatory networks" that determine susceptibility to neurodegeneration in AD. We expect that identified genetic networks will include a combination of disease modifier genes in AD and novel therapeutic targets to halt AD progression by preventing neurodegeneration.

Figure 1 Integration of systems and experimental biology to understand the pathogenesis of Alzheimer’s disease

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Chief: Koichi M. Iijima, PhD

Research fellow: Michiko Sekiya, PhD

Research specialist: Yasufumi Sakakibara, PhD

Postdoctral fellow: Xiuming Quan, PhD

Graduate student D3: Naoki Fujisaki, MS

Research technician: Sachie Chikamatsu, MS



Koichi M. Iijima, Ph.D.


B. S.: The University of Tokyo, 1996 
Ph. D.: The University of Tokyo, 2001
Postdoctoral training: Cold Spring Harbor Laboratory, New York, USA, 2001-2006

Assistant Professor & Laboratory Head: Thomas Jefferson University, Department of Neuroscience, Philadelphia, USA, 2006-2013

Principal Investigator & Laboratory Head: National Center for Geriatrics and Gerontology, Department of Alzheimer's Disease Research, Obu, Aichi, Japan, 2013-

Visiting Associate Professor, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan, 2013-

External link to Nagoya City University Graduate School of Pharmaceutical  Sciencesこのリンクは別ウィンドウで開きます

External link to Experimental Gerontologyこのリンクは別ウィンドウで開きます

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1) To elucidate molecular mechanisms underlying the pathogenesis of Alzheimer's disease through integrated biology approach

   Alzheimer’s disease (AD) is the leading cause of dementia and a progressive neurodegenerative disorder. AD is characterized by aggregation and accumulation of two proteins, amyloid-β peptides (Aβ) and the microtubule-associated protein tau. Lines of evidence support the concept that the elevated level of Aβ peptides is a very early, often initiating factor, which lies upstream of tau to drive synaptic dysfunction and neurodegeneration. Although this cascade of events plays a central role in AD pathogenesis, progression of AD is a complicated process resulting from the interplay of a number of genetic and environmental factors. System-level analyses of large datasets from patients have emerged as powerful tools for understanding complex diseases such as AD. Gene expression datasets, along with genomic and clinical information, from multiple studies have been accumulated, and data interpretation is becoming to one of the most difficult challenges in these omics approaches.

   Gene regulatory network analysis is a powerful tool in identifying gene modules pathologically related to human complex diseases including AD (Zhang, B. et al., Cell 2013). In collaboration with Dr. Bin Zhang at Icahn School of Medicine at Mount Sinai, we utilized gene co-expression network analysis to capture pathological changes in molecular interactions of cellular pathways as differential connectivity (Zhang, B. et al., Cell 2013, Wang, M. et al., Genome Medicine 2016). Through integration of AD brain networks and gene expression signatures and experimental validation data from the latest fly and mouse models of AD (Iijima, K., et. al., PNAS 2004, Saito, T., et. al., Nat Neurosci 2014), our laboratory is trying to decipher complex AD pathogenesis at cellular and gene network levels (Sakakibara, Y., Sekiya, M. et. al., PLOS Genetics 2018, Sekiya, M., Wang, M. et. al., Genome Med. 2018 ) (Figure 1).

Figure 1 Integration of systems and experimental biology to understand the pathogenesis of Alzheimer’s disease

   The goal of our study is to identify "gene regulatory networks" that determine susceptibility to neurodegeneration in AD. We expect that identified genetic networks will include a combination of disease modifier genes in AD and novel therapeutic targets to halt AD progression by preventing neurodegeneration. Furthermore, in collaboration with the Department of Drug Discovery, we are keen to expand our findings to translational research.  


2) Genome-wide screen using next-generation Drosophila models of Alzheimer's disease

   Drosophila has been used as a powerful genetic model system in many fields of biology and proven to be highly informative to understand human neurodegenerative diseases. Analysis of the Drosophila genome has revealed that many genes and pathways are conserved between human and flies and approximately 70% of human disease-related genes have homologs in Drosophila. With the short generation time, large number of progeny and the sophisticated genetic tools available, one of the most important tools that Drosophila provides is the ability to perform a large number of genetic interaction studies as well as unbiased genome-wide screens.

   I established the first-generation, Drosophila models of Alzheimer’s disease expressing human Aβ42 in 2004 (Iijima, K., et. al., PNAS 2004). These fly models have been used in many laboratories all over the world to study the mechanisms underlying Aβ42 toxicity. With recent advances in detailed understanding of AD pathogenesis, we generated the next-generation fly models of AD to better recapitulate AD pathogenesis. These fly models will be integrated with our experimental validation study and also serve platforms for genome-wide screen to identify novel disease modifier genes in AD.


3) To elucidate the initial step of mismetabolism of microtubule associated protein tau in Alzheimer's disease

   Accumulation of the microtubule-associated protein tau in neurons is associated with a number of neurodegenerative diseases including Alzheimer’s disease (AD). Tau abnormality is thought to induce neuronal death in these diseases. However, how tau abnormality starts, progresses and eventually causes neuronal death are not fully understood. Elucidation of these processes at molecular levels may reveal an efficient therapeutic strategy for AD.

   Tau is phosphorylated at multiple sites in Alzheimer’s disease brains. We found that tau phosphorylation at AD-related Ser262/356 stabilized microtubule-unbound tau. Phosphorylation at these sites stabilized tau detached from microtubules, and blocking phosphorylation at these sites suppressed tau accumulation and tau-induced neurodegeneration (Ando, K. et. al. 2016 PLoS Genetics, etc). These results suggest that stabilization of tau by phosphorylation at Ser262/356 may act in the initial steps of tau mismetabolism and tau-induced neuronal death in disease pathogenesis.

   Currently, our projects focus on mechanisms underlying tau phosphorylation at Ser262/356 and stabilization of tau phosphorylated at those sites. These studies will reveal mechanisms underlying tau-mediated neurodegeneration and may identify potential drug targets for AD.  


4) To elucidate molecular logics underlying stress signaling networks and their application to age-related degenerative diseases

   Multiple anti-stress signaling pathways have evolved to maximize reproduction and survival in the presence of various environmental stressors. During pathogenesis of chronic human diseases, these mechanisms are activated as protective responses. However, canonical stress signaling networks often fail to prevent disease conditions, presumably because they are not optimized for aging or complex diseases. For example, in many age-associated degenerative disorders, accumulation of misfolded proteins acts as chronic stressors. The canonical anti-stress signaling are activated as protective responses, however, sustained activation of them often results in active removal of stressed cells and tissue damages, which eventually contribute to disease progression.

   These evidence suggest that elucidation of molecular logics of anti-stress signaling networks and their temporal regulation are crucial to understand mechanisms underlying many age-associated degenerative diseases. Moreover, there is also a possibility that cells may be able to counteract chronic diseases if selective components of, but not whole, anti-stress signaling are expressed. If this is the case, genetic or pharmacological modification of canonical anti-stress signaling pathways represents a novel strategy for counteracting age-associated chronic diseases.

   The unfolded protein response (UPR) in the ER is one of the anti-stress responses often associated with age-related neurodegenerative diseases. We are currently investigating molecular logics and temporal regulation of UPR and aim to identify the minimal functional unit of ER-associated degradation using Drosophila as a genetic model system (Sekiya, M. et. al., 2017, Developmental Cell, 2017).

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1. Sakakibara, Y., Sekiya, M., Saito, T., Saido, T.C. & Iijima, K.M. (2018) Cognitive and emotional alterations in App knock-in mouse models of Aβ amyloidosis. BMC Neurosci., 2018 Jul 28;19(1):46. doi: 10.1186/s12868-018-0446-8.

2. Chiku, T., Hayashishita, M., Saito, T., Oka, M., Shinno, K., Ohtake, Y., Shimizu, S., Asada, A., Hisanaga, S., Iijima, K.M., & Ando, K. (2018) S6K/p70S6K1 protects against tau-mediated neurodegeneration by decreasing the level of tau phosphorylated at Ser262 in a Drosophila model of tauopathy. Neurobiol. Agingin press

3. 飯島浩一,関谷倫子 (2018) アルツハイマー病の発症機序研究〜TREM2/TYROBPから見えてきたアルツハイマー病発症機序〜 Animus 2018 No.96 p.13-17

4. Sekiya, M.*, Wang, M.*, Fujisaki, N., Sakakibara, Y., Quan, X., Ehrlich, M.E., De Jager, P.L., Bennett, D.A., Schadt, E.E., Gandy, S., Ando, K., Zhang, B., & Iijima, K.M. (2018) Integrated biology approach reveals molecular and pathological interactions among Alzheimer's Aβ42, Tau, TREM2, and TYROBP in Drosophila models. Genome Med., 2018 Mar29;10(1):26., *Co-first authors

5. Sakakibara, Y.*, Sekiya, M.*, Fujisaki, N., Quan, X., & Iijima, K.M. (2018) Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in Drosophila. PLOS Genetics, 14(1): e1007196, *Co-first authors

6. Satoh, A. & Iijima, K.M. (2018) Roles of tau pathology in the locus coeruleus (LC) in age-associated pathophysiology and Alzheimer’s disease pathogenesis. (Review) Brain Research, 2017 Dec 21. pii: S0006-8993(17)30562-0. doi: 10.1016/j.brainres.2017.12.027

7. Sekiya, M., Maruko-Otake, A., Hearn, S., Fujisaki, N., Sakakibara, Y., Suzuki, E., Ando, K. & Iijima, K.M. (2017) EDEM function in ERAD protects against chronic ER proteinopathy and age-related physiological decline in Drosophila. Developmental Cell, 41 (6) 652-664. e5, 19 June 2017          

8. Oka, M., Fujisaki, N.,Maruko-Otake, A., Ohtake, Y., Shimizu, S., Saitoh T., Hisanaga, S., Iijima, K.M. & Ando, K. (2017) Ca2+/calmodulin-dependent protein kinase II promotes neurodegeneration caused by tau phosphorylated at Ser262/356 in a transgenic Drosophila model of tauopathy. J. Biochem., DOI:

9. 岡未来子, 飯島浩一, 安藤香奈絵 (2017) 神経細胞内のミトコンドリア局在異常と認知症, 実験医学, 認知症: 発症前治療のために解明すべき分子病態は何か?, Vol. 35, No.12, p182-p185

10. Ando, K., Oka, M., Ohtake, M., Hayashishita, M., Shimizu,S., Hisanaga, S. & Iijima, K.M. (2016) Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated. Biochem Biophys Res Commun, 478(2):929-34. doi:10.1016/j.bbrc.2016.08.053. Epub 2016 Aug 9

11. 関谷倫子,飯島浩一 (2016) 統合生物学的手法によるアルツハイマー型神経細胞死の機序解明とその抑止法, Dementia Japan, 30巻, 2号, 246-256

12. Ando, K., Maruko-Otake, A., Otake, Y., Sekiya, M. & Iijima, K.M. (2016) Stabilization of microtubule-unbound tau via tau phosphorylation at Ser262/356 by Par-1/MARK contributes to augmentation of AD-related phosphorylation and Aβ42-induced tau toxicity. PLOS Genetics, 12(3): e1005917

13. 関谷倫子, 飯島浩一 (2016) システム生物学を用いてアルツハイマー病を遺伝子ネットワークから読み解く(総説), ファルマシア, Vol. 52 No. 2, p121-126

14. Ando, K., Suzuki E. Hearn, A., Sekiya, M., Maruko-Otake, A. & Iijima, K.M. (2015) Electron microscopy of the brains of Drosophila models of Alzheimer's disease, Neuromethods, Transmission Electron Microscopy Methods for Understanding the Brain, Springer, DOI 10.1007/7657_2015_75

15. Mendoza, J., Sekiya, M., Taniguchi, T., Iijima, M.K., Wang, R., and Ando, K. (2013) Global Analysis of Phosphorylation of Tau by the Checkpoint Kinases Chk1 and Chk2 in vitro, Journal of Proteome Research, 12(6):2654-65

16. Iijima-Ando, K., Sekiya, M., Maruko-Otake, A., Ohtake, Y., Suzuki, E., Lu, B., and Iijima, K.M. (2012) Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1, PLOS Genetics, 8(8): e1002918

17. Iijima, K. and Iijima-Ando, K. (2011) Transgenic Drosophila models of Alzheimer's amyloid-beta 42 toxicity, Handbook of Animal Models in Alzheimer's Disease: G. Casadesus (Ed.), IOS Press., 89-106

18. Iijima, K., Gatt, A. and Iijima-Ando, K. (2010) Tau Ser262 phosphorylation is critical for Abeta42-induced tau toxicity in a transgenic Drosophila model of Alzheimer's disease, Hum. Mol. Genet., 19:2947-57. Epub 2010 May 12

19. Iijima-Ando, K., Zhao, L., Gatt, A., Shenton, C., and Iijima, K. (2010) A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration, Hum. Mol. Genet., 19: 1930-1938

20. Iijima, K., Zhao, L., Shenton, C., and Iijima-Ando, K. (2009) Regulation of energy stores and feeding by neuronal and peripheral CREB activity in Drosophila, PLOS ONE, 4(12): e8498

21. Iijima-Ando, K. and Iijima, K. (2009) Transgenic Drosophila models of Alzheimer's disease and tauopathies, (review article), Brain Struct. Funct., 214(2-3):245-62, Epub 2009 Dec 5

22. Iijima-Ando, K., Hearn, S.A., Shenton, C., Gatt, A., Zhao, L. and Iijima, K. (2009) Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease, PLOS ONE, 4(12): e8310 

23. Lee, K-S., Iijima-Ando, K., Iijima, K., Lee, W-J., Lee, J.H., Yu, K., and Lee, D-S. (2009) JNK/FOXO-mediated neuronal expression of fly homologue of Peroxiredoxin II reduces oxidative stress and extends lifespan in Drosophila, J. Biol. Chem., 284, 29454-61

24. Iijima, K., Iijima-Ando, K., and Zhong, Y. (2009) Drosophila model of Alzheimer's amyloidosis, Chapter 14, Handbook of Behavior Genetics, Springer

25. Chiang, H., Iijima, K., Hakker, I., and Zhong, Y. (2009) Distinctive roles of different beta-amyloid 42 aggregates in modulation of synaptic functions. FASEB J, 23(6):1969-77

26. Iijima, K., and Iijima-Ando, K. (2008) Drosophila models of Alzheimer amyloidosis; the challenge of dissecting the complex mechanisms of toxicity of amyloid-beta 42. (Review article) Journal of Alzheimer Disease, 15(4):523-40

27. Iijima-Ando, K., Hearn, S.A., Granger, L., Shenton, C., Gatt, A., Chiang, H.C., Hakker, I., Zhong, Y., and Iijima, K. (2008). Overexpression of Neprilysin Reduces Alzheimer Amyloid beta-42 (Abeta42)-induced Neuron Loss and Intraneuronal Abeta42 Deposits but Causes a Reduction in cAMP-responsive Element-binding Protein-mediated Transcription, Age-dependent Axon Pathology, and Premature Death in Drosophila.  J. Biol. Chem. 283, 19066-19076

28. Iijima, K., Chiang, H. C., Hearn, S. A., Hakker, I., Gatt, A., Shenton, C., Granger, L., Leung, A., Iijima-Ando, K., and Zhong, Y. (2008) Abeta42 mutants with different aggregation profiles induce distinct pathologies in Drosophila. PLOS ONE 3, e1703

29. Sano, Y., Nakaya, T., Pedrini, S., Furukori, K., Iijima-Ando, K., Iijima, K., Mathews, P.M., Itohara, S., Gandy, S, and Suzuki, T. (2006) Physiological mouse brain amyloid-beta levels are not related to the phosphorylation state of threonine-668 of Alzheimer APP. PLOS ONE, 1, e51

30. Iijima-Ando, K., Wu, P., Drier, A., Iijima, K. & Yin, J.C.P. (2005) CREB and HSP70 additively suppress polyglutamine-induced toxicity in Drosophila. Proc. Natl. Acad. Sci. 102, 10261-6

31. Asaumi, M., Iijima, K., Sumioka, A.,Iijima-Ando, K., Kirino, Y., Nakaya, T. & Suzuki, T. (2005) Interaction of N-terminal acetyltransferase with the cytoplasmic domain of beta-amyloid precursor protein and its effect on Abeta secretion. J. Biochem. (Tokyo). 137(2):147-55

32. Iijima, K., Liu, H-P., Chiang, A-S., Hearn, S. A., Konsolaki, M. & Zhong, Y. (2004) Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: A potential model for Alzheimer disease. Proc. Natl. Acad. Sci. 101, 6623-6628

33. Taru, H., Iijima, K., Hase, M., Kirino, Y., Yagi, Y., & Suzuki, T. (2002) Interaction of Alzheimer beta-Amyloid Precursor Family Proteins with Scaffold Proteins of the JNK Signaling Cascade. J. Biol. Chem. 277, 20070-78

34. Ando, K., Iijima, K., Elliott, J.L., Kirino, Y., & Suzuki, T. (2001) Phosphorylation-dependent regulation on the interaction of amyloid precursor protein with Fe65 and the production of beta-amyloid. J. Biol. Chem. 276, 40353-61

35. Iijima, K., Ando, K., Takeda, S., Satoh, Y., Seki, T., Itohara, S., Greengard, P., Narin, A.C., Kirino, Y. & Suzuki, T. (2000). Neuron-specific phosphorylation of Alzheimer amyloid precursor protein by Cdk5. J. Neurochem. 75, 1085-91

36. Suzuki, T., Ando, K., Iijima, K., Oguchi, S., Takeda, S. (1999). Phosphorylation of Amyloid Precursor Protein (APP) Family Proteins. Alzheimer's Disease Methods and Protocols, Methods in Molecular Medicine, Vol 32, 271-282

37. Ando, K., Oishi, M., Takeda, S., Iijima, K., Isohara, T., Narin, A.C., Kirino, Y., Greengard, P., & Suzuki, T. (1999). Role of phosphorylation of Alzheimer amyloid precursor protein during neuronal differentiation. J Neurosci. 19, 4421-7

38. Watanabe,T., Sukegawa, J., Sukegawa, I., Tomita, S., Iijima, K., Oguchi, S., Suzuki, T., Nairn, A.C., & Greengard, P. (1999). A 127-kDa protein (UV-DDB) binds to the cytoplasmic domain of the Alzheimer amyloid precursor protein. J. Neurochem. 72, 549-56

39. Iijima, K, Lee, D.S., Okutsu, J., Tomita, S., Hirashima, N., Kirino, Y., & Suzuki, T. (1998) cDNA isolation of Alzheimer amyloid precursor protein from cholinergic nerve terminals of the electric organ of the electric ray. Biochem. J. 330, 29-33


Educational activity

   We proactively encourage education and training for young researchers in the field of Alzheimer's disease. We affiliate with Nagoya City University, Graduate School of Phamaceutical Sciences (External linkこのリンクは別ウィンドウで開きます) and are happy to accept highly motivated graduate students to conduct their research. If you are interested in joining our lab, please contact Dr. Iijima via email.

Koichi M. Iijima, PhD

Visiting Associate Professor, Nagoya City University, Graduate School of Phamaceutical Sciences

E-mail: iijimakm (at)


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Koichi M. Iijima, Ph.D.

Tel: 0562-46-2311 (ext 7505/6408)

E-mail: iijimakm (at)


Access to NCGG

7-430, Morioka-machi, Obu City, Aichi 474-8511, Japan

About 30 minutes by car from the Chubu International Airport (Centrair)

Access to NCGG



  • National Center for Geriatrics and Gerontology
  • National Hospital for Geriatric Medicine, NCGG
  • Research Institute, NCGG
  • Center for Gerontology and Social Science

National Center for Geriatrics and Gerontology

7-430 Morioka-cho, Obu City, Aichi Prefecture, Japan