| Co-Investigator(Kenkyū-buntansha) |
MAEDA Kiyoshi Kobe University, Graduate School of Medicine, Professor, 医学部, 教授 (80116251)
ONO Yoshitaka Kobe University, Biosignal Research Center, Professor, バイオシグナル研究センター, 教授 (10243297)
MUKAI Hideyuki Kobe University, Biosignal Research Center, Associate Professor, バイオシグナル研究センター, 助教授 (80252758)
TAKAHASHI Mikiko Kobe University, Biosignal Research Center, Lecturer, バイオシグナル研究センター, 講師 (90324938)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2004: ¥3,100,000 (Direct Cost: ¥3,100,000)
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| Research Abstract |
Neuronal localization of a large complex inteacting with some kinases and phosphatases, which phosphorylate or dephosphorylate tau protein directly, was investigated to clarify the mechanism underlying neuronal degeneration seen in brain tissues of the patients with degenerative dementia including Alzheimer's disease (AD) and fronto-temporal dementia (FTD). These kinases include PKN, PKC, PKA and Casein kinase 1 delta, and the phosphatases include PP1, PP2A and PP2B. In primary cultured brain tissues and the brains from mice, rats, human controls and the demented patients, the complex molecule was localized immunohistochemically only in neurons. Study for subcellular localization revealed that the complex was distributed in the cytoplasm within neuronal cell bodies and proximal neuritis in normal tissues. By contrast, it was accumulated within neurofibrillary tangles and degenerative neuritis in AD brains, and also accumulated within ballooned cell bodies of residual neurons in FTD brains.
In addition, neuropathological examinations were performed in some patients with familial dementia. Neuronal loss accompanied by axonal dystrophy and glial activations was remarkable in the hippocampus and frontal, parietal and occipital lobes in the brain of a patient with hereditary sensory neuropathy type 1 with deafness and dementia, while some patients with tau P301S mutation showed pathological changes in frontal and temporal lobes and subcortical nuclei, which consisted of neuronal loss, microvacuolation, astrocytic fibrosis, neuropil threads, ballooned neurons and glial fibrillary tangles.
Thus, our results suggest a specific role of the interacting molecule with tau-kinases and phosphatases in neurodegeneration in the dementia including AD and FTD.
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