Attempt to develop animal model for the formation of paired helical filaments in the brains of Alzheimer's disease patients via sustained inactivation of integrin-linked kinase in mouse brain.

尝试开发动物模型，通过小鼠大脑中整合素连接激酶的持续失活，在阿尔茨海默病患者的大脑中形成配对螺旋丝。

• 批准号: 16380195
• 负责人: ISHII Toshiaki
• 金额: $ 9.92万
• 依托单位: Obihiro University of Agriculture and Veterinary Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16380195/
• 关键词: ILK; paired helical filament; Alzheimer's disease; animal model; tau; aberrant phosphorylation; brain; learning and memory; タウタンパク質; 痴呆

Integrin-linked kinase (ILK) is a focal adhesion serin/threonine protein kinase with an important role in integrin and growth factor signaling pathways. Recently, we demonstrated that ILK inactivation results in aberrant tau phosphorylation, which is identical to some of the aberrant phosphorylation sites in paired helical filaments in the brains of patients with Alzheimer's disease, via sustained activation of GSK-3β in cultured N1E-115 cells. In this study, we examined whether sustained inactivation of ILK leads to aberrant tau phosphorylation and produces paired helical filaments in mouse brain. Transfection and expression of a kinase-deficient mutant of ILK (DN-ILK), which behaves as a dominant negative, to mouse brain in vivo lead to inhibition of ILK activity and increase in active form of GSK-3β, and then induce aberrant tau phosphorylation in the hippocampus 3 wk after the transfection. However, the inhibition of endogenous ILK activity induced by DN-ILK is not retained and recovered to the basal level via a marked increase of endogenous ILK protein 12 wk after DN-ILK transfection. This compensatory mechanism leads the active form of GSK-3β to normal level and results in a decrease in the levels of aberrant tau phosphorylation. These results strongly suggest that ILK protects against aberrant tau phosphorylation via inhibition of GSK-3β activity in vivo. Although we could not create the mouse model for paired helical filaments in the brains of patients with Alzheimer's disease, our results imply that medical drugs to activate ILK activity might be effective in the therapy of patients with the early stage of Alzheimer's disease. Further studies are required to elucidate the compensatory mechanism after ILK inactivation in the brain.

整合素连接蛋白激酶(ILK)是一种粘着斑丝氨酸/苏氨酸蛋白激酶，在整合素和生长因子信号转导通路中发挥重要作用。最近，我们通过在培养的N1E-115细胞中持续激活GSK-3β，证明了ILK失活会导致tau的异常磷酸化，这与阿尔茨海默病患者大脑中成对螺旋细丝中的一些异常磷酸化位点相同。在这项研究中，我们研究了ILK的持续失活是否会导致tau的异常磷酸化，并在小鼠大脑中产生成对的螺旋细丝。将显性阴性的ILK突变体(DN-ILK)转入小鼠脑内表达，可抑制ILK活性，增加GSK-3β的活性，并在3wk后诱导海马区tau蛋白异常磷酸化。但对内源性ILK活性的抑制作用未被保留，而是通过内源性ILK蛋白的显著增加而恢复到基础水平。这种代偿机制导致β的活性形式恢复到正常水平，并导致tau异常磷酸化水平的降低。这些结果有力地表明，ILK通过抑制体内GSK-3的β活性来保护tau的异常磷酸化。尽管我们无法在阿尔茨海默病患者的大脑中建立成对螺旋细丝的小鼠模型，但我们的结果表明，激活ILK活性的药物可能对阿尔茨海默病早期患者的治疗有效。脑内ILK失活后的代偿机制尚需进一步研究。

项目成果

A competitive effect of androgen signaling on male mouse attraction to volatile female mouse odors.

雄激素信号传导对雄性小鼠对挥发性雌性小鼠气味的吸引力的竞争作用。

• 发表时间: 2006
• 期刊: Physiol. Behay. 87
• 作者: Tragami T;Kagami H;Matsubara Y;Harumi T;Naito M;Takeda K;Hanada H;Nirasawa K;Yoshikage Muroi
• 通讯作者: Yoshikage Muroi