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Laboratory of Disease Control
Kimura group
Nobuyuki Kimura, D.V.M., Ph.D. >> 
Research Area
Nowadays, Alzhemier’s disease (AD), a progressive neurological disorder that is histopathologicaly characterized by the formations of senile plaques (SPs) and neurofibrillary tangles (NFTs), is becoming a world-wide problem. There are two types in AD, one is familial AD (FAD) caused by mutant genes, and the other is sporadic AD (SAD) caused by aging. More than 80% of AD patients belong to SAD, but the mechanism of its onset still remains unknown.
Cynomolgus monkey is one of the nonhuman primates, and we can find spontaneous SP formations in aged brains. Moreover, the homology of deduced amino acid sequences of amyloid b (Ab), the major component of SP, in comparison with that in humans is 100%; thus, the cynomolgus monkey would be considered as a useful animal model to investigate Ab pathology.
In this section, we have been investigating age-related changes of AD-associated proteins by using monkey brains for clarifying the SAD pathogenesis and the influence of aging on neural system. We also keep working on the establishment of primate animal models not only for AD but also for other aging-causative neurodegenerative disorders.
<< Senile plaque in aged cynomolgus monkey brain.
Senile plaque (SP) :
SPs are mainly composed by amyloid b pepteide (Ab) . Ab is a mainly 40- to 42-amino-acid peptide processed by cleavage of 695- to 770-amino-acid membrane-associated glycoprotein, termed bamyloid precursor protein (APP).
In normal human brains, SPs can be found already in the late of 40’s or 50’s.
Research Subjects
1.Investigation of age-related changes of neuronal functions
In our previous studies, we found that AD-associated proteins accumulated in synapse fraction with aging. We hypothesize that these synaptic protein accumulations might be caused by the aging-causative impairment of intracellular axonal transport system in neurons, and we are now investigating the association between its system and aging.

2.Investigation of astroglial functions in AD pathology
Astrocytes, the mosst abundant glial cell types in the brain, are affected by Ab, and have an important role in clearing Ab from the brain. We have previously shown that astroglial responses against Ab occurred before obvious neuronal damages were found, and this finding suggests that the role of astrocytes in early stage of AD pathology must be very important, and astrocytes could be the therapeutic target for AD. Thus we are investigating the astroglial function in AD pathology by using cultured rat and cynomolgus monkey astrocytes.

Recent Our Findings
<< Photomicrographs of temporal lobe sections from a 4-year-old cynomolgus monkey.
In sections from the young monkey , anti-Ab antibody immunostained cortical neurons in a granular fashion.
(This is the first study showing that intracellular Ab localized in young animal neurons.)
<< Western blots showing the accumulation of intracellular Ab in nerve ending fractions from brains of various aged cynomolgus monkeys.
<< The amount of total intracellular Ab& in the nerve ending fraction significantly increased with age.
Key: 4, 4-year-old monkey (N=4); 20+, 20- to 21-year-old (N=4); and 30+, 30- and 36-year-old monkeys (N=2). *p<0.02.

These findings show that intracellular Ab accumulates in the nerve ending fraction with age, and closely parallels our findings with other AD-related proteins reported in our previous studies.
Taken together, it is suggested that the accumulation of intracellular Ab would cause the onset of AD pathology.
Selected Publications
  • Kimura N, Yanagisawa K, Terao K, Ono F, Sakakibara I, Ishii Y, Kyuwa S, Yoshikawa Y.
    Age-related changes of intracellular Abeta in cynomolgus monkey brains.
    Neuropathol Appl Neurobiol. 2005 Apr;31(2):170-80.
  • Kimura N, Negishi T, Ishii Y, Kyuwa S, Yoshikawa Y.
    Astroglial responses against Abeta initially occur in cerebral primary cortical cultures: species differences between rat and cynomolgus monkey.
    Neurosci Res. 2004 Jul;49(3):339-46.
  • 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.
    A seed for Alzheimer amyloid in the brain.
    J Neurosci. 2004 May 19;24(20):4894-902.
  • Kimura N, Nakamura S, Ono F, Sakakibara I, Ishii Y, Kyuwa S, Yoshikawa Y.
    Presenilin-2 in the cynomolgus monkey brain: investigation of age-related changes.
    Primates. 2004 Jul;45(3):167-75. Epub 2004 Feb 18.
  • Kimura N, Tanemura K, Nakamura S, Takashima A, Ono F, Sakakibara I, Ishii Y, Kyuwa S, Yoshikawa Y.
    Age-related changes of Alzheimer's disease-associated proteins in cynomolgus monkey brains.
    Biochem Biophys Res Commun. 2003 Oct 17;310(2):303-11.
  • Kimura N, Nakamura SI, Honda T, Takashima A, Nakayama H, Ono F, Sakakibara I, Doi K, Kawamura S, Yoshikawa Y.
    Age-related changes in the localization of presenilin-1 in cynomolgus monkey brain.
    Brain Res. 2001 Dec 13;922(1):30-41.
Contact
Nobuyuki Kimura, D.V.M., Ph.D.

Laboratory of Disease Control,
Tsukuba Primate Research Center,
National Institute of Biomedical Innovation,
Hachimandai 1-1, Tsukuba-shi, Ibaraki 305-0843, Japan
TEL: +81-29-837-2121
FAX: +81-29-837-0218
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