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Aging Research(Partnership field)Cognitive Function Research

Introduction

This department is based on the system of linked graduate school between National Center for Geriatrics and Gerontology and Nagoya University. We are conducting researches mainly focusing on molecular basic study on the pathogenesis of Alzheimer’s disease and clinical and experimental aspects of mild cognitive impairment (MCI). For the former subject, we are aiming at elucidating metabolism (synthesis and degradation) of amyloid ß-protein and its precursor protein (APP) using various cellular and animal models.
For the second subject, we are studying MCI patients to find protective factors for brain that are useful for dementia prevention. From the year 2017, we started multiple factor prevention trials of MCI.

Research Projects

(1) Molecular pathogenesis of Alzheimer’s disease

i) 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. 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.

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ii) 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.

iii) Type II diabetes mellitus and AD pathology.

Several epidemiological and clinical studies showed that type II diabetes mellitus (T2DM) patients are more likely to develop cognitive dysfunction and 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 even in cynomolgus monkey brains accompanied by enhanced endocytic pathology, suggesting that T2DM aggravates age-related endocytic pathology in the brain. In this study, we try to reveal the pathological mechanism how T2DM enhances AD pathology, especially for endocytic dysfunction. We also investigate T2DM-related alterations in glial cells and their functions.

(2) Multifactorial intervention for preventing dementia

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For the prevention of dementia, the first target is to control the pathological changes of the brain including neuronal degeneration and vascular lesions. On the other hand, “protective factor for brain” has been recently attracting much attention. In order to maintain healthy brain function, physical exercise, nutrition, social activity, and vitality as well as management of lifestyle disease are important. These protective factors are based on functional association between the brain and body organs. Up until today, we have been analyzing the huge database at memory clinic of NCGG, to find the nature of these protective factors. From the year 2017, we have started interventional trial by intervening on these multiple factors simultaneously to prevent progression from MCI to dementia.

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Also, we started a new study aiming for genomic medicine of dementia by collaborating with the Medical Genome Center at NCGG. We are accumulating data-set of global genomic analysis on dementia patients. We expect energetic researchers from Nagoya University to utilize these data.

Faculty Members

FacultyPositionDepartment
NAKAMURA, Akinori Visiting Professor Cognitive Function Research
SAKURAI, Takashi Visiting Professor Cognitive Function Research

Bibliography

  • 2016
    1. Japan Diabetes Society (JDS)/Japan Geriatrics Society (JGS) Joint Committee on Improving Care for Elderly Patients with Diabetes. Glycemic Targets for Elderly Patients with Diabetes. J Diabetes Investig, in press
    2. Fujisawa C, Umegaki H, Nakashima H, Okamoto K, Kuzuya M, Toba K, Sakurai T. Postural Function Decline at Earlier Stages of Alzheimer's Disease Compared to Gait Function and Grip Strength Decline. J Am Med Dir Assoc, in press
    3. Ueda N, Tomota T, Yanagisawa K, Kimura N. Retromer and Rab2-dependent trafficking mediate PS1 degradation by proteasomes in endocytic disturbance. J Neurochem, 2016; 137: 647-658.
    4. Saji N, Sakurai T, Suzuki K, Mizusawa H, Toba K, on behalf of the ORANGE investigators. ORANGE's challenge: Developing a wide-ranging dementia registry in Japan. Lancet Neurology, 2016; 15: 661-662.
    5. Sakurai T, Arai H, Toba K. Japan’s challenge of early detection of persons with cognitive decline. J Am Med Dir Assoc, 2016; 17(5): 451-452.
    6. Sugimoto T, Ono R, Murata S, Saji N, Matsui Y, Niida S, Toba K, Sakurai T. Prevalence and associated factors of sarcopenia in elderly subjects with amnestic mild cognitive impairment or Alzheimer disease. Curr Alzheimer Res, 2016; 13: 718-726.
    7. Seike A, Sakurai T, Sumigaki C, Takeda A, Endo H, Toba K. Verification of Educational Support Intervention for Family Caregivers of Persons with Dementia. J Am Geriatr Soc, 2016; 64: 661-663.
  • 2015
    1. kabayashi S, Shimozawa N, Yasutomi Y, Yanagisawa K, Kimura N. Diabetes mellitus accelerates Aβ pathology in brain accompanied by enhanced GAβ generation in nonhuman primates. PLoS ONE, 2015; 10(2): e0117362.
    2. Oikawa N, Matsubara T, Fukuda R, Yasumori H, Hatsuta H, Murayama S, Sato T, Suzuki A, Yanagisawa K. Imbalance in fatty-acid-chain length of gangliosides triggers Alzheimer amyloid deposition in the precuneus. PLoS ONE, 2015; 10(3): e0121356.
    3. Wang X, Hu X, Yang Y, Takata T, Sakurai T. Systemic pyruvate administration markedly reduces neuronal death and cognitive impairment in a rat model of Alzheimer's disease. Exp Neurol, 2015; 271: 145-154.
    4. Sakurai T, Tomimoto H, Pantoni L. A new horizon of cerebral white matter hyperintensity in geriatric medicine. Geriatr Gerontol Int, 2015; 15: 1-2.
    5. Yasue M, Sugiura S, Uchida Y, Otake H, Teranishi M, Sakurai T, Toba K, Shimokata H, Ando F, Otsuka R, Nakashima T. Prevalence of Sinusitis Detected by Magnetic Resonance Imaging in Subjects with Dementia or Alzheimer’s Disease. Curr Alzheimer Res, 2015; 12: 1006-1011.
  • 2014
    1. Kaneko N, Nakamura A, Washimi Y, Kato T, Sakurai T, Arahata Y, Bundo M, Takeda A, Niida S, Ito K, Toba K, Tanaka K, Yanagisawa K. Novel plasma biomarker surrogating cerebral amyloid deposition. Proc Jpn Acad Ser B Phys Biol Sci, 2014; 90: 353-364.
    2. Hong S, Ostaszewski BL, Yang T, O'Malley TT, Jin M, Yanagisawa K, Li S, Bartels T, Selkoe DJ. Soluble Aβ Oligomers Are Rapidly Sequestered from Brain ISF In Vivo and Bind GM1 Ganglioside on Cellular Membranes. Neuron, 2014; 82: 308-319.
    3. Oikawa N, Hatsuta H, Murayama S, Suzuki A, Yanagisawa K. Influence of APOE genotype and the presence of Alzheimer's pathology on synaptic membrane lipids of human brains. J Neurosci Res, 2014; 92: 641-650.
    4. Ogama N, Sakurai T, Shimizu A, Toba K. Regional white matter lesions predict falls in patients with amnestic mild cognitive impairment and Alzheimer's disease. J Am Med Dir Assoc, 2014; 15: 36-41.
  • 2012
    1. Oikawa N, Goto M, Ikeda K, Taguchi R, and Yanagisawa K. The γ-secretase inhibitor DAPT increases the levels of gangliosides at neuritic terminals of differentiating PC12 cells. Neurosci Lett, 2012; 525: 49-53.
    2. Wang X, Takata T, Bai X, Ou F, Yokono K, Sakurai T. Pyruvate Prevents the Inhibition of the Long-term Potentiation Induced by Amyloid-β through Protein Phosphatase 2A Inactivation. J Alzheimers Dis, 2012; 29: 1-9.
    3. Araki A, Iimiro S, Sakurai T, Umegaki H, Iijima K, Nakano H, Oba K, Yokono K, Sone H, Yamada N, Ako J, Kozaki K, Miura H, Kashiwagi A, Kikkawa R, Yoshimura Y, Nakano T, Ohashi Y, Ito H. Long-term multiple risk factor interventions in Japanese elderly diabetic patients: The Japanese Elderly Diabetes Intervention Trial (J-EDIT)–study design, baseline characteristics and effects of intervention. Geriatr Gerontol Int, 2012; 12: 7-17.
  • 2010
    1. Wang XN, Song X, Takata T, Yokono K, Sakurai T. Amyloid-β neurotoxicity restricts glucose window for neuronal survival in rat hippocampal slice cultures. Exp Gerontol, 2010; 45: 904-908.
    2. Sakurai T, Iimuro S, Araki A., Umegaki H, Ohashi Y, Yokono K, Ito H. Age-associated increase in abdominal obesity and insulin resistance, and usefulness of AHA/NHLBI definition of metabolic syndrome for predicting cardiovascular disease in Japanese elderly with type 2 diabetes mellitus. Gerontology, 2010; 56: 141-149.
  • 2009
    1. Yuyama K, and Yanagisawa K. Late endocytic dysfunction as a putative cause of amyloid fibril formation in Alzheimer’s disease. J Neurochem, 2009; 109: 1250-1260.
    2. Sakurai T, Taniguchi H, Nambu S, Tokuda M, Makibayashi T, Yokono K, Endo H. Education of lifestyle risk factors associated with dementia likely to help primary care physicians to improve consultation for elderly people with dementia. J Am Geriatr Soc, 2009; 57(12): 2358-2361.
  • 2008
    1. Yuyama K, Yamamoto N, and Yanagisawa K. Accelerated release of exosome-associated GM1 ganglioside (GM1) by endocytic pathway abnormality: another putative pathway for GM1-induced amyloid fibril formation. J Neurochem, 2008; 105: 217-224.
    2. Yamamoto N, Matusbara T, Sato T, and Yanagisawa K. Age-dependent high-density clustering of GM1 ganglioside at presynaptic neuritic terminals promotes amyloid β-protein fibrillogenesis. Biochim Biophys Acta, 2008; 1778: 2717-2726.
    3. Umegaki H, Iimuro S, Kaneko T, Araki A, Sakurai T, Ohashi Y, Iguchi A, Ito H. Factors associated with lower mini mental state examination scores in elderly Japanese diabetes mellitus patients. Neurobiol Aging, 2008; 29: 1022-1026.
  • 2007
    1. Yamamoto N, Matsubara E, Maeda S, Minagawa H, Takashima A, Maruyama W, Michikawa M, and Yanagisawa K. A ganglioside-induced toxic soluble Aβ assembly: Its enhanced formation from Aβ bearing the Arctic mutation. J Biol Chem, 2007; 282: 2646-2656.
    2. Yamamoto N, Fukata Y, Fukata M, and Yanagisawa K. GM1-ganglioside-induced Aβ assembly on synaptic membranes of cultured neurons. Biochim Biophys Acta, 2007; 1768: 1128-1137.
    3. Kimura N, and Yanagisawa K. Endosomal accumulation of GM1-ganglioside-bound amyloid β-protein in neurons of aged monkey brains. Neuroreport, 2007; 18: 1669-1673.
  • 2006
    1. Yuyama K, Yamamoto N, and Yanagisawa K. Chloroquine-induced endocytic pathway abnormalities: cellular model of GM1-ganglioside-induced Aβ fibrillogenesis in Alzheimer’s disease. FEBS Lett, 2006; 580: 6972-6976.
    2. Kidoguchi K, Tamaki M, Takashi M, Koyama J, Kondoh T, Kohmura E, Sakurai T, Yokono K, Umetani K. In Vivo X-ray Angiography in the Mouse Brain using Synchrotron Radiation. Stroke, 2006; 37:1856-1861.
    3. Akisaki T, Sakurai T, Takata T, Umegaki H, Araki A, Mizuno S, Tanaka S, Ohashi Y, Iguchi A, Yokono K and Ito H. Cognitive dysfunction associates with white matter hyperintensities and subcortical atrophy on magnetic resonance imaging of the elderly diabetes mellitus Japanese Elderly Diabetes Intervention Trial (J-EDIT). Diabetes Metab Res Rev, 2006; 22: 376-384.
  • 2005
    1. Kimura N, Yanagisawa K, Terao K, Ono F, Sakakibara I, Ishii Y, Kyuwa S, and Yoshikawa Y. Age-related changes of intracellular Aβ in cynomolgus monkey brains. Neuropathol Applied Neurobiol, 2005; 31: 170-180.
  • 2004
    1. 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, and Yanagisawa K. A seed for Alzheimer amyloid in the brain. J Neurosci, 2004; 24: 4894-4902.
  • 2002
    1. Komano H, Kawamura Y, Shiraishi H, Sai X, Suzuki R, Kawaichi M, Kitamura T, and Yanagisawa K. A new functional screening system for the identification of cDNA encoding a regulator of γ-cleavage. J Biol Chem, 2002; 277: 39627-39633.
    2. Sakurai T, Yang B, Takata T, Yokono K. Synaptic adaptation to repeated hypoglycemia depends on the utilization of monocarboxylates in guinea pig hippocampal slices. Diabetes, 2002; 51: 430-438.
  • 2001
    1. Michikawa M, Gong J-S, Fan Q-W, Sawamura N, and Yanagisawa K. A novel action of Alzheimer’s amyloid β-protein (Aβ): oligomeric Aβpromotes lipid efflux. J Neurosci, 2001; 21: 7226-7235.
  • 2000
    1. Hayashi H, Mizuno T, Michikawa M, Haass C, and Yanagisawa K. Amyloid precursor protein in unique cholesterol-rich microdomains different from caveolae-like domains. Biochim Biophys Acta, 2000; 1483: 81-90.
  • 1999
    1. Mizuno T, Nakata M, Naiki H, Michikawa M, Wang R, Haass C, and Yanagisawa K. Cholesterol-dependent generation of a seeding amyloid β-protein in cell culture. J Biol Chem, 1999; 274: 15110-15114.
    2. Sakurai T, Akiyama H, Oka T, Sekita K, Yokono K, Goto T. Serum lipids status in patients with diabetic uremia on 10 years of maintenance hemodialysis. Kidney Int. Suppl, 1999; 216-218.
  • 1998
    1. Mizuno T, Haass C, Michikawa M, and Yanagisawa K. Cholesterol-dependent generation of a unique amyloid β-protein from apically missorted amyloid precursor protein in MDCK cells. Biochim Biophys Acta, 1998; 1373: 119-130.
  • 1996
    1. Sakurai T, Westenbroek RE, Rettig J, Hell JW, Catterall WA. Biochemical properties and subcellular distribution of the BI and rbA isoforms of α1A subunits of brain calcium channels. J Cell Biol, 1996; 134: 511-528.
  • 1995
    1. Yanagisawa K, Odaka A, Suzuki N, and Ihara Y. GM1 ganglioside-bound amyloid β-protein (Aβ): A possible form of preamyloid in Alzheimer's disease. Nature Med, 1995; 1: 1062-1066.

Research Keywords

Alzheimer's disease、 amyloid ß-protein、 APP、 MCI、 diabetes、 prevention