2000 Fiscal Year Final Research Report Summary
Study of the mechanism of abnormal phosphorylation of Alzheimer's disease.
| Project/Area Number |
11557184
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | The University of Tokushima |
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Principal Investigator |
YAMAUCHI Takashi The University of Tokushima, Faculty of Pharmaceutical Sciences, Department of Biochemistry, Professor, 薬学部, 教授 (90041813)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIMURA Yoshiyuki The University of Tokushima, Faculty of Pharmaceutical Sciences, Department of Biochemistry, Assistant Professor., 薬学部, 助手 (20035554)
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| Project Period (FY) |
1999 – 2000
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| Keywords | abnormal phosphorylation / Alzheimer's disease / calmodulin / CaM kinase II / neural differentiation / protein kinase / tau protein |
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| Research Abstract |
In Alzheimer's disease (AD), microtubule-associated protein tau becomes abnormally phosphorylated and aggregates into paired helical filaments (PHFs). The biochemical mechanism of stimulation of tau phosphorylation and tau aggregation remaines unclear. To investigate the mechanism of hyperphosphorylation of tau, we studied its phosphorylation using neuroblastoma cells overexpressing several protein kinases. The following results were obtained in this study ; (1) Cell lines expressing Ca^<2+>/calmodulin-dependent protein kinase II (CaM kinase II) were prepared, and Cam kinase II promoted neurite outgrowth. (2) The differentiation of neuronal cells were regulated by CaM kinase II and protein kinase C.(3) Ca^<2+>-independent activity of the kinase autophosphorylated at Thr-286 involved for neurite outgrowth. (4) The expression of δ isoform of CaM kinase II was induced, and the splicing pattern of the isoform changed, during neural differentiation of P19 cells. (5) Cell type distinctive changes of splicing pattern of δ isoform were observed not only during differentiation of cultured neuronal cells, but also during development of rat forebrain and cerebellum. (6) Cell lines of P19 expressing human tau cDNA were obtained, and abnormal neural differentiation of P19 cell induced by retinoic acid, and these cells were thought to be as useful model of AD.(7) Tau protein was produced by E.coli and used it as substrate of various protein kinases. The condition forming insoluble tau was investigated using purified tau. (8) The protein kinase that phosphorylated specific sites of AD tau was investigated in the aged brain and differentiated neuroblastoma cells. Present study provide some insight of the phosphorylation of tau and role of tau on neuronal differentiation.
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