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Section of Cell Biology and Pathology

Introduction

   Since aging is the biggest risk factor for Alzheimer’s disease (AD), it is quite important to
clarify the age-related pathological mechanism. Moreover, mutations in certain genes are
causative for familila AD, and metabolic disorders, such as type 2 diabetes mellitus, also
induce susceptibility to AD.
   In AD patient brains, there are two pathological hallmarks such as senile plaques (SPs) and
neurofibrillary tangles (NFTs). SP is the extracellular deposition of β-amyloid protein (Aβ),
and NFT is the intracellular accumulation of microtubule-associated protein tau.
   Although AD is a human-specific disease, SPs and NFTs are also observed in aged animal  
brains. In cynomolgus monkey brains, both SPs and NFTs occur spontaneously with advancing  
age, and the amino acid sequence of Aβ is completely consistent with that of humans.
These advantages make this species a useful model to study age-dependent AD pathology.
   Thus we are investigating cynomolgus monkey brains to understand age-related changes
in brains, and we also conduct cell biological studies to understand how risk factors induce
AD pathology for developing the brand-new preventive/therapeutic tools.

​                                                                                     E-mail: kimura (at) ncgg.go.jp

Figure: AD and risk factors

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Research Topic

Endocytic dysfunction and AD pathology

   Cytoplasmic dynein is a microtubule-based motor protein required for minus end-directed
axonal transport. Dynactin, another microtubule-associated protein, binds to dynein to
form a functional complex that enables motor activity.
   We have previously found that aging attenuates the interaction between dynein and
dynactin in cynomolgus monkey brains, and dynein dysfunction induces the intracellular
accumulation of Aβ via endocytic dysfunction. Aβ cleavage from its precursor protein mainly
occurs in endosomes, and several endocytosis-related genes were identified as risk factors for
AD by recent genetic studies. Moreover, our recent finding suggests that diabetes mellitus
exacerbates age-related endocytic dysfunction, leading to accelerate Aβ​ pathology.
   We consider that endocytic dysfunction is one of the causative factors for age-dependent
AD pathology, and such “traffic jam” would be a preventive/therapeutic target.

Figure: Traffic Jam Hypothesis

AD risk factors and endocytosis

   Presenilin 1 (PS1) is the catalytic core of the γ-secretase complex, which is indispensable
for Aβ cleavage, and mutations of PS1 are the predominant cause of familial AD (FAD). 
Intriguingly, severe endocytic pathology is observed in FAD patient neurons, suggesting
that mutations of PS1 may be causative for endocytic dysfunction.
   Several epidemiological and clinical studies showed that type II diabetes mellitus (T2DM)
patinets are more likely to exhibit increased susceptibility to AD. Other groups also reported
that there are several similarities and connections between the pathology observed
in the brains of AD and DM patients. Recently, we found that T2DM accelerates Aβ pathology
in cynomolgus monkey brains accompanied by enhanced endocytic pathology, suggesting that
T2DM also aggravates age-related endocytic pathology in the brain.
   Hence, we are working on the study to reveal the pathological mechanism how risk factors
affect endocytosis, leading to exacerbate age-related endocytic dysfunction.
We are also investigating T2DM-related alterations in glial cells and their functions.

Aging and Tau pathology

   Even in cynomolgus monkey brains, we can find age-dependent NFT formation.
Our recent study showed that tau accumulates in brain age-dependently and a ~30kDa
cleaved tau is the main component of insoluble aggregation.
   Although a large number of studies showed that the posttranscriptional modifications,
such as phosphorylation, induces tau aggregation, it remains unclear why tau abnormally
accumulates in AD patient brains.
   In this study, we aim to clarify the mechanism of age-related accumulation and truncation
of tau in brain. Moreover, we also investigate the relationship between intracellular transport
deficit and tau pathology.

 

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Member

Member photo

Nobuyuki Kimura, D.V.M., Ph.D. (Chief; center)

Shingo Takeuchi, Ph.D. (Research fellow; left)

Yukako Tsuchiya (Research Assistant; right)

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Publications

1. Uchihara T, Endo K, Kondo H, Okabayashi S, Shimozawa N, Yasutomi Y, Adachi E, Kimura N. (2016) Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX Acta Neuropathol Comm,4(1): 118.

2. Kimura N. (2016) Diabetes mellitus induces Alzheimer’s disease pathology: histopathological evidence in animal models Int J Mol Sci,17(4): 503.

3. Kimura N, Samura E, Suzuki K, Okabayashi S, Shimozawa N, Yasutomi Y. (2016) Dynein Dysfunction Reproduces Age-Dependent Retromer Deficiency: Concomitant Disruption of Retrograde Trafficking Is Required for Alteration in APP Metabolism Am J Pathol, 186(7): 1952-1966.

4. Ueda N, Tomita T, Yanagisawa K, Kimura N. (2016) Retromer and Rab2-dependent trafficking mediate PS1 degradation by proteasomes in endocytic disturbance J Neurochem, 137(4): 647-658.

5. Ishiguro A, Kimura N, Watanabe Y, Watanabe S, Ishihama A. (2016) TDP-43 recognizes RNA G-quadruplex structures, and controls neurite mRNA transport for local protein synthesis Genes Cells, 21(5): 466-481.

6. Okabayashi S, Shimozawa N, Yasutomi Y, Yanagisawa K, Kimura N. (2015) Diabetes mellitus accelerates Aβ pathology in brain accompanied by enhanced GAβ generation in nonhuman primates PLoS ONE, 10(2): e0117362.

7. Yuyama K, Sun H, Usuki S, Sakai S, Hanamatsu H, Mioka T, Kimura N, Okada M, Tahara H, Furukawa J, Fujitani N, Shinohara Y, Igarashi Y. (2015) A potential function for neuronal exosomes: sequestering intracerebral amyloid-β peptide. FEBS Lett, 589(1): 84-88.

8. Kimura N, Okabayashi S, Ono F. (2014) Dynein dysfunction disrupts Aβ clearance in astrocytes via endocytic disturbances. Neuroreport, 25(7): 514-520.

9. Morihara T, Hayashi N, Yokokoji M, Akatsu H, Silvermana MA, Kimura N, Sato M, Saito Y, Suzuki T, Yanagida K, Kodama TS, Tanaka T, Okochi M, Tagami S, Kazui H, Kudo T, Hashimoto R, Itoh N, Nishitomi K, Kabata-Yamagichi Y, Tsunoda T, Takamura H, Katayama T, Kimura R, Kamino K, Hashizume Y, Takeda M. (2014) Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid beta accumulation modifier. PNAS, 111(7): 2638-2643.

10. Kimura N, Okabayashi S, Ono F. (2012) Dynein dysfunction disrupts intracellular vesicle trafficking bidirectionally and perturb synaptic vesicle docking via endocytic disturbances: a potential mechanism underlying age-dependent impairment of cognitive function. Am J Pathol, 180(2): 550-561.

11. Uchida A, Sasaguri H, Kimura N, Ono F, Sakaue F, Hirai T, Tajiri M, Kanai K, Ohkubo T, Sano T, Shibuya K, Kobayashi M, Ueno T, Sunaga F, Ikeda S, Kubodera T, Tomori M, Sakaki K, Kusano K, Enomoto M, Yokota S, Hirai Y, Yasutomi Y, Uchihara T, Kuwabara S, Mizusawa H, Yokota T. (2012) Non-human primate model of ALS with cytoplasmic mislocalization of TDP-43. Brain, 135(3): 833-846.

12. Matsushima T, Saito Y, Elliott JI, Iijima-Ando K, Nishimura M, Kimura N, Hata S, Yamamoto T, Nakaya T, Suzuki T. (2012) Membrane-microdomain localization of amyloid β-precursor protein (APP) C-terminal fragments is regulated by phosphorylation of the cytoplasmic Thr668 residue. J Biol Chem, 287(23): 19715-19724.

13. Nishimura M, Nakamura S, Kimura N, Liu L, Suzuki T, Tooyama I. (2012) Age-related modulation of γ-secretase activity in non-human primate brains. J Neurochem, 123(1): 21-28.

14. Okabayashi S, Kimura N. (2010) LGI3 interacts with flotillin-1 to mediate APP trafficking and exosome formation. Neuroreport, 21(9): 606-610.

15. Oikawa N, Kimura N, Yanagisawa K. (2010) Alzheimer-type tau pathology in advanced aged nonhuman primate brains harboring substantial amyloid depositio. Brain Res, 1315: 137-149.

16. Kimura N, Inoue M, Okabayashi S, Ono F, Negishi T. (2009) Dynein dysfunction induces endocytic pathology accompanied by an increase in Rab GTPases: a potential mechanism underlying age-dependent endocytic dysfunction. J Biol Chem, 284(45): 31291-31302.

17. Okabayasi S, Kimura N. (2008) Leicine-rich glioma inactivated 3 is involved in amyloid β peptide uptake by astrocytes and endocytosis itself. Neuroreport, 19(12): 1175-1179

18. Kimura N, Yanagisawa K. (2007) Endosomal accumulation of GM1-ganglioside- bound amyloid β-protein in neurons of aged monkey brains. Neuroreport, 18(16): 1669-1673

19. Okabayashi S, Kimura N. (2007) Immunohistochemical and biochemical analyses of LGI3 in monkey brain: LGI3 accumulates in aged monkey brains. Cell Mol Neurobiol, 27(6): 819-830

20. Kimura N, Imamura O, Ono F, Terao K. (2007) Aging attenuates dynactin-dynein interaction: down-regulation of dynein causes accumulation of enodogenous tau and APP in human neuroblastoma cells. J Neurosci Res, 85(13): 2909-2916

21. Kimura N, Ishii Y, Suzaki S, Negishi T, Kyuwa S, Yoshikawa Y. (2007) Aβ upregulates and colocalizes with LGI3 in cultured rat astrocytes. Cell Mol Neurobiol, 27(3): 335-350

22. Kimura N, Takahashi M, Tashiro T, Terao K. (2006) Amyloid β up-regulates brain-derived neurotrophic factor production from astrocytes: rescue from amyloid β-related neuritic degeneration. J Neurosci Res, 84(4): 782-789.

23. Kimura N, Yanagisawa K, Terao K, Ono F, Sakakibara I, Ishii Y, Kyuwa S, Yoshikawa Y. (2005) Age-related changes of intracellular Abeta in cynomolgus monkey brains. Neuropathol Appl Neurobiol, 31(2): 170-180.

24. Kimura N, Negishi T, Ishii Y, Kyuwa S, Yoshikawa Y. (2004) Astroglial responses against Abeta initially occur in cerebral primary cortical cultures: species differences between rat and cynomolgus monkey. Neurosci Res, 9(3): 339-46.

25. Hayashi H, Kimura N, Yamaguchi H, Hasegawa K, Yokoseki T, Shibata M, Yamamoto N, Michikawa M, Yoshikawa Y, Terao K, Matsuzaki K, Lemere CA, Selkoe DJ, Naiki H, Yanagisawa K. (2004) A seed for Alzheimer amyloid in the brain. J Neurosci, 4(20): 4894-902.

26. Kimura N, Tanemura K, Nakamura S, Takashima A, Ono F, Sakakibara I, Ishii Y, Kyuwa S, Yoshikawa Y. (2003) Age-related changes of Alzheimer’s disease-associated proteins in cynomolgus monkey brains. Biochem Biophys Res Commun, 10(2): 303-11.

27. Kimura N, Nakamura S, Honda T, Takashima A, Nakayama H, Ono F, Sakakibara I, Doi K, Kawamura S, Yoshikawa Y. (2001) Age-related changes in the localization of presenilin-1 in cynomolgus monkey brain. Brain Res, 922(1): 30-41.

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  • 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

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