Animal Model for Evaluation of Druge on Therapeutics of Alzheimer Disease

评价药物治疗阿尔茨海默病的动物模型

• 批准号: 09470208
• 负责人: TAKEDA Masatoshi
• 金额: $ 8.26万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-09470208/
• 关键词: Alzheimer Disease; Presenilin; Endoplasmic Reticulum; Aging; Aβ(Amyloid β); GFAP (Grially Fibrillary Acidic Protein); aging; Aβ; ノックインマウス; 点突然変異

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.

我们成功地建立了早老素-1基因突变（I213 T）的敲入小鼠模型。Aβ42/Aβ40比值升高。免疫组化结果显示，在30周、8个月和24个月，该模型小鼠无老年斑或神经纤维缠结，但在该模型小鼠海马中观察到抗GFAP抗体阳性星形胶质细胞的增加，并呈基因剂量依赖性。在Western blot分析中也观察到抗GFAP抗体染色的增加。此外，在大脑皮质的II和III层的神经元中观察到细胞内Aβ42的增加。这些结果表明，PS-1突变和衰老协同诱导阿尔茨海默病脑内星形胶质细胞增多和细胞内Aβ42积聚，原代培养的该模型小鼠神经元对内质网应激反应减弱。在表达突变型早老素的细胞中，伴侣蛋白GRP 78的表达降低，ER应激的传感蛋白Ire 1的功能减弱。因此，这些细胞比没有突变早老素的细胞更容易诱导凋亡。阐明了突变型早老素神经变性的部分机制。

项目成果

Takashi Kudo et al: "Are cerebrovascular factors involved in Alzheimer's disease?"Neurobio.Aging. 21. 215-224 (2000)

Takashi Kudo 等人：“脑血管因素与阿尔茨海默病有关吗？”Neurobio.Aging。

Takashi Kudo et al: "Are cerebrovascular factors involved in Alzheimer's disease?"Neurobio. Aging. 21. 215-224 (2000)

Takashi Kudo 等人：“脑血管因素与阿尔茨海默病有关吗？”Neurobio。

T.Katayama et al.: "Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response"Nat Cell Biolog. 8. 479-485 (1999)

T.Katayama 等人：“Presenilin-1 突变下调未折叠蛋白反应的信号传导途径”Nat Cell Biolog。

H.Tanimukai et al.: "Alzheimer-associated presenilin 1 gene is induced in gerbil hippocampus after transient ischemia" Mol.Brain Res.(in press)

H.Tanimukai 等人：“短暂性缺血后，沙鼠海马中会诱导阿尔茨海默病相关的早老素 1 基因”Mol.Brain Res.（出版中）

武田雅俊 他: "わが国における家族性アルツハイマー病" 老年精神医学雑誌. 8(6). 565-570 (1997)

Masatoshi Takeda 等人：“日本的家族性阿尔茨海默病”《老年精神病学杂志》8(6) (1997)。