2000 Fiscal Year Final Research Report Summary
Animal Model for Evaluation of Druge on Therapeutics of Alzheimer Disease
| Project/Area Number |
09470208
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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 | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | Osaka University |
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Principal Investigator |
TAKEDA Masatoshi Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (00179649)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Toshihisa Osaka University Graduate School of Medicine, Assiatant Professor, 医学系研究科, 助手 (10294068)
NAKAMURA Yu Osaka University Graduate School of Medicine, Assiatant, 医学系研究科, 助手 (70291440)
KUDO Takashi Osaka University Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (10273632)
TAKEDA Junji Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (50163407)
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| Project Period (FY) |
1997 – 2000
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| Keywords | Alzheimer Disease / Presenilin / Endoplasmic Reticulum / Aging / Aβ(Amyloid β) / GFAP (Grially Fibrillary Acidic Protein) |
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| Research Abstract |
We succeeded in making a knock-in mouse model that has mutant presenilin-1 gene (I213T). An increase of the ratio of Aβ42/Aβ40 was observed in this model mouse. Immunohistochemical study showed no senile plaque or no neurofibrillary tangle in this mouse in 30 weeks, 8 months, and 24 months, however an increase of anti-GFAP antibody-positive astrocytes was observed in hippocampus of this model mouse in the gene-dose dependent manner. An increase of anti-GFAP antibody staining was also observed in Western bolt analysis. Furthermore an increase of intracellular Aβ42 was observed in neurons was observed in the II and III layers of cerebral cortex. These results suggest that PS-1 mutation and aging synergetically induce increase of astrocytes and accumulation of intracellular Aβ42 that are usually observed in Alzheimer brains.
Primary cultured neurons derived from this model mouse showed decreased responses to ER (endoplasmic reticulum) stresses. The expression of GRP78, one of chaperone protein, was decreased and Ire 1, an sensor protein to ER stress, was less functioning, in cells with expression of mutant presenilin. Therefore apoptosis was more easily induced in these cells than in cells without mutant presenilin. A part of mechanisms on neurodegeneration in mutant presenilin was clarified.
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