BACE inhibitor reduces APP-β-C-terminal fragment accumulation in axonal swellings of okadaic acid-induced neurodegeneration
BACE inhibitor reduces APP-β-C-terminal fragment accumulation in axonal swellings of okadaic acid-induced neurodegeneration
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DOI：
10.1016/j.nbd.2005.12.013
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发表时间：
2006-05
影响因子：
6.1
通讯作者：
Seung-Yong Yoon;Jung-Eun Choi;JuHee Yoon;J. Huh;Dong Hou Kim
中科院分区：
文献类型：
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作者：
Seung-Yong Yoon;Jung-Eun Choi;JuHee Yoon;J. Huh;Dong Hou Kim
新出现的证据表明，不仅β-淀粉样蛋白，而且其他淀粉样蛋白前体蛋白（APP）片段，如β- c末端片段（βCTF），可能与阿尔茨海默病（AD）有关。用蛋白磷酸酶2a抑制剂okadaic acid （OA）处理神经元，可以诱导tau磷酸化和神经元死亡，从而建立AD的研究模型。在本研究中，我们分析了OA处理的培养大鼠神经元的轴突病变和APP调节。OA处理后，神经元出现轴突肿胀，充满囊泡、微管碎片和转运分子，如运动蛋白和突触素- 1。Western blotting结果显示细胞内APP水平升高，应用APP c端抗体免疫细胞化学结果显示APP在轴突肿胀处积聚。当神经元与β-分泌酶抑制剂共处理时，APP c端免疫反应性消失，而与α-或γ-分泌酶抑制剂共处理时则没有，表明积累主要由APP-β ctf组成。这些发现首次证明APP-βCTF可在经oa处理的神经元轴突中积累，并可能提示APP-βCTF参与了AD的发病机制。
Emerging evidence suggests that not only β-amyloid but also other amyloid precursor protein (APP) fragments, such as the β-C-terminal fragment (βCTF), might be involved in Alzheimer's disease (AD). Treatment of neurons with okadaic acid (OA), a protein phosphatase-2A inhibitor, has been used to induce tau phosphorylation and neuronal death to create a research model of AD. In this study, we analyzed axonopathy and APP regulation in cultured rat neurons treated with OA. After OA treatment, the neurons presented with axonal swellings filled with vesicles, microtubule fragments, and transport molecules such as kinesin and synapsin-I. Western blotting showed that intracellular APP levels were increased and immunocytochemistry using antibodies against the APP C-terminus showed that APP accumulated in the axonal swellings. This APP C-terminus immunoreactivity disappeared when neurons were cotreated with a β-secretase inhibitor, but not with α- or γ-secretase inhibitors, indicating that the accumulation was primarily composed of APP-βCTF. These findings provide the first evidence that APP-βCTF can accumulate in the axons of OA-treated neurons, and may suggest that APP-βCTF is involved in the pathogenesis of AD.