The cytoplasmic domain of Alzheimer's amyloid-β protein precursor causes sustained apoptosis signal-regulating kinase 1/c-Jun NH2-terminal kinase-mediated neurotoxic signal via dimerization
The cytoplasmic domain of Alzheimer's amyloid-β protein precursor causes sustained apoptosis signal-regulating kinase 1/c-Jun NH2-terminal kinase-mediated neurotoxic signal via dimerization
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DOI：
10.1124/jpet.103.051383
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发表时间：
2003-09-01
影响因子：
3.5
通讯作者：
Nishimoto, I
中科院分区：
文献类型：
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作者：
Hashimoto, Y;Niikura, T;Nishimoto, I
全长β淀粉样蛋白前体（AbetaPP）（Abeta的前体）的生物学功能尚不完全清楚。多个实验室报告称，抗体与细胞表面 AbetaPP 结合会导致神经元细胞死亡。在这里，我们检查了 AbetaPP (AbetaPP(CD)) 细胞质结构域的诱导二聚化是否会触发神经元细胞死亡。在表达表皮生长因子 (EGF) 受体与 AbetaPP(CD) 融合结构的神经杂交细胞中（EGFR/AbetaPP 杂交体），EGF 以对乙酰基-L-天冬氨酰-L-谷氨酰-L-缬氨酰-L-天冬氨酰-醛（Ac-DEVD-CHO；DEVD）、GSH-乙酯（GEE）和百日咳毒素（PTX）敏感的方式显着增强神经元细胞死亡。显性负性凋亡信号调节激酶 1 (ASK1) 可以阻断这种神经元细胞死亡，但不能阻断 α-突触核蛋白诱导的细胞死亡。组成型活性 ASK1 (caASK1) 以对 PTX 耐药且对护脑素敏感的方式引起 DEVD/GEE 敏感细胞死亡，这也通过 EGFR/AbetaPP 杂交抑制神经元细胞死亡。 ASK1 通过 JIP-1b（c-Jun N 末端激酶 (JNK) 相互作用蛋白）与 AbetaPP(CD) 形成复合物。 EGFR/AbetaPP 杂种诱导的和 caASK1 诱导的神经元细胞死亡可被 SP600125（anthra[1,9-cd]pyrazol-6(2H)-one）（一种特异性 JNK 抑制剂）特异性阻断。结合我们早期的研究，这些数据表明 AbetaPP CD 的二聚化触发了 ASK1/JNK 介导的神经元细胞死亡。我们还注意到 ASK1/JNK 在 AbetaPP 初始激活后维持该机制活性的潜在作用，这允许通过短期抗 AbetaPP 抗体治疗实现细胞死亡。了解 AbetaPP(CD) 及其下游通路的功能应该有助于开发有效的抗阿尔茨海默病疗法。
The biological function of full-length amyloid-beta protein precursor (AbetaPP), the precursor of Abeta, is not fully understood. Multiple laboratories have reported that antibody binding to cell surface AbetaPP causes neuronal cell death. Here we examined whether induced dimerization of the cytoplasmic domain of AbetaPP (AbetaPP(CD)) triggers neuronal cell death. In neurohybrid cells expressing fusion constructs of the epidermal growth factor (EGF) receptor with AbetaPP(CD) (EGFR/AbetaPP hybrids), EGF drastically enhanced neuronal cell death in a manner sensitive to acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspartyl-aldehyde (Ac-DEVD-CHO; DEVD), GSH-ethyl ester (GEE), and pertussis toxin (PTX). Dominant-negative apoptosis signal-regulating kinase 1 (ASK1) blocked this neuronal cell death, but not alpha-synuclein-induced cell death. Constitutively active ASK1 (caASK1) caused DEVD/GEE-sensitive cell death in a manner resistant to PTX and sensitive to Humanin, which also suppressed neuronal cell death by EGFR/AbetaPP hybrid. ASK1 formed a complex with AbetaPP(CD) via JIP-1b, the c-Jun N-terminal kinase (JNK)-interacting protein. EGFR/AbetaPP hybrid-induced and caASK1-induced neuronal cell deaths were specifically blocked by SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one), a specific JNK inhibitor. Combined with our earlier study, these data indicate that dimerization of AbetaPP CD triggers ASK1/JNK-mediated neuronal cell death. We also noticed a potential role of ASK1/JNK in sustaining the activity of this mechanism after initial activation by AbetaPP, which allows for the achievement of cell death by short-term anti-AbetaPP antibody treatment. Understanding the function of AbetaPP(CD) and its downstream pathway should lead to effective anti-Alzheimer's disease therapeutics.