Molecular characterization of neurohybrid cell death induced by Alzheimer's amyloid-β peptides via p75NTR/PLAIDD
Molecular characterization of neurohybrid cell death induced by Alzheimer's amyloid-β peptides via p75NTR/PLAIDD
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DOI：
10.1111/j.1471-4159.2004.02513.x
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发表时间：
2004-08-01
影响因子：
4.7
通讯作者：
Nishimoto, I
中科院分区：
文献类型：
--
作者：
Hashimoto, Y;Kaneko, Y;Nishimoto, I
阿尔茨海默病(AD)最重要的病理特征之一是细胞外老年斑，其主要成分是淀粉样β-多肽(Abeta)。Aβ与p75NTR(p75神经营养素受体)的胞外区结合，诱导神经细胞死亡。我们从p75NTR与其近亲PLAIDD(p75样细胞凋亡诱导死亡结构域)相互作用的角度详细研究了Abeta诱导神经毒性的分子机制。利用F11神经元杂交细胞，我们证明了p75NTR介导的Abeta诱导的毒性有两条不同的途径。已阐明的一条途径是由p75NTR、GO、JNK、NADPH氧化酶和caspase3相关的caspase介导的。我们发现PLAIDD和GI蛋白这两种异源三聚体G蛋白参与了p75NTR介导的Abeta诱导的选择性神经毒性。因此，由Abeta触发的替代途径是由p75NTR、PLAIDD、GI、JNK、NADPH氧化酶和caspase3相关的caspase介导的。此外，我们还发现HN、ADNF、IGF-I或bFGF可抑制p75NTR介导的Abeta诱导的神经毒性的两条通路。
One of the most important pathological features of Alzheimer's disease (AD) is extracellular senile plaques, whose major component is amyloid-beta peptides (Abeta). Abeta binds to the extracellular domain of p75NTR (p75 neurotrophin receptor) and induces neuronal cell death. We investigated the molecular mechanism of Abeta-induced neurotoxicity in detail from the standpoint of interaction between p75NTR and its recently identified relative, PLAIDD (p75-like apoptosis-inducing death domain). Using F11 neuronal hybrid cells, we demonstrate that there are two distinct pathways for Abeta-induced toxicity mediated by p75NTR. One pathway that has been previously elucidated, is mediated by p75NTR, Go, JNK, NADPH oxidase and caspase3-related caspases. We found that PLAIDD and Gi proteins, heterotrimeric G proteins, are involved in the alternative Abeta-induced neurotoxicity mediated by p75NTR. The alternative pathway triggered by Abeta is thus mediated by p75NTR, PLAIDD, Gi, JNK, NADPH oxidase and caspase3-related caspases. In addition, we found that HN, ADNF, IGF-I, or bFGF inhibits both pathways of Abeta-induced neurotoxicity mediated by p75NTR.