Development of diagnostic and therapeutic strategies for Alzheimer's disease : focus on a novel cerebral amyloid component

阿尔茨海默病诊断和治疗策略的开发：关注新型脑淀粉样蛋白成分

• 批准号: 12558088
• 负责人: IWATSUBO Takeshi
• 金额: $ 7.94万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12558088/
• 关键词: Alzheimer; collagen; amyloid; CLAC; アルツハイマー病

We raised monoclonal antibodies against senile plaque (SP) amyloid and obtained a clone 9D2, which labeled amyloid fibrils in SP and reacted with 50/100 kDa polypeptides in Alzheimer's disease (AD) brains. We purified the 9D2 antigens and cloned a cDNA encoding its precursor, which was a novel type II transmembrane protein specifically expressed in neurons. This precursor harbored three collagen-like Gly-X-Y repeat motifs, prompting us to designate 9D2 antigen CLAC (collagen-like Alzheimer amyloid plaque component), and its precursor CLAC-P (CLAC-precursor). The extracellular domain of CLAC-P was secreted by furin convertase (sCLAC), and the ammo terminus of CLAC in AD brains was pyroglutamate-modified. sCLAC and CLAC-P specifically bound to fibrillized Aβ, implicating CLAC/CLAC-P in β- amyloidogenesis and neuronal degeneration in AD.

我们提出了针对老年斑（SP）淀粉样蛋白的单克隆抗体，并获得了克隆9D 2，它标记的淀粉样蛋白纤维在SP和50/100 kDa的多肽在阿尔茨海默病（AD）的大脑反应。我们纯化了9D 2抗原，并克隆了编码其前体的cDNA，这是一种在神经元中特异性表达的新型II型跨膜蛋白。这种前体含有三个胶原样Gly-X-Y重复基序，促使我们命名为9D 2抗原CLAC（胶原样阿尔茨海默淀粉样斑块组分）及其前体CLAC-P（CLAC前体）。CLAC-P的胞外区由弗林蛋白酶转化酶（sCLAC）分泌，其氨基末端被焦谷氨酸修饰。sCLAC和CLAC-P特异性结合于纤维化的Aβ，暗示CLAC/CLAC-P在AD中的β-淀粉样蛋白生成和神经元变性中。

项目成果

Takeuchi A,Irizarry MC,Duff K,Saido TC,Hsiao Ashe K,Hasegawa M,Mann DMA,Hyman BT,Iwatsubo T: "Age-related amyloid_deposition in transgenic mice overexpressing both presenilin 1 and amyliod_precursor protein Swedish mutant is not associated with global neu

Takeuchi A、Irizarry MC、Duff K、Saido TC、Hsiao Ashe K、Hasekawa M、Mann DMA、Hyman BT、Iwatsubo T：“过表达早老素 1 和淀粉样前体蛋白的转基因小鼠中与年龄相关的淀粉样蛋白沉积瑞典突变体与全球性淀粉样蛋白沉积无关”

Saura CA,Tomita T,Soriano S,Takahashi M,Leem J-Y,Honda T,Koo EH,Iwatsubo T,Thinakaran G: "The non-conserved hydrophilic loop domain of presenilin is neither required for presenilin endoproteolysis nor enhanced A_42 production mediated by FAD-linked PS var

Saura CA、Tomita T、Soriano S、Takahashi M、Leem J-Y、Honda T、Koo EH、Iwatsubo T、Thinakaran G：“早老素的非保守亲水环结构域既不是早老素内切蛋白水解所必需的，也不是 FAD 介导的增强 A_42 产生所必需的

Tomita T: "The first proline of PALP motif at the C terminus of presenilins is obligatory for stabilization, complex formation and γ-secretase activities of presenilins"J Biol Chem. 276. 33273-33281 (2001)

Tomita T：“早老素 C 末端 PALP 基序的第一个脯氨酸对于早老素的稳定、复合物形成和 γ-分泌酶活性是必需的”J Biol Chem 276. 33273-33281 (2001)

Iwatsubo T: "Amyloid deposits and plaque formation Neurodegenerative Dementias. Edited by Christopher M. Clark and John Q. Trojanowski."McGraw-Hill. 10 (2000)

Iwatsubo T：“淀粉样蛋白沉积和斑块形成神经退行性痴呆。由 Christopher M. Clark 和 John Q. Trojanowski 编辑。”McGraw-Hill。

Hashimoto T: "CLAC : a novel Alzheimer amyloid plaque component derived from a transmembrane precursor, CLAC-P/collagen type XXV"EMBO J.. 21. 1524-1534 (2002)

Hashimoto T：“CLAC：一种源自跨膜前体 CLAC-P/XXV 型胶原的新型阿尔茨海默淀粉样斑块成分”EMBO J.. 21. 1524-1534 (2002)