Department of Anatomy and Neuroscience, College of Medicine, Eulji University, Daejeon 301-746, Republic of Korea.
Department of Emergency Medical Technology, Daejeon University, Daejeon 34520, Republic of Korea.
Exp Mol Pathol. 2021 Jun;120:104622. doi: 10.1016/j.yexmp.2021.104622. Epub 2021 Mar 6.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by neuronal and synaptic loss. The cytoplasmic tail of amyloid precursor protein (APP) undergoes sequential cleavage at a specific intracellular caspase site to generate the cytoplasmic terminal 31 (CT31) fragment. The APP-CT31 fragment is a potent inducer of apoptosis. The cytotoxicity of APP-CT31 in SH-SY5Y cells was evaluated by the lactate dehydrogenase (LDH) assay. TUNEL staining was used to detect apoptotic signals in SH-SY5Y cells and primary cortical neurons. The expression of apoptosis-related proteins, such as p53, PUMA (p53 up-regulated modulator of apoptosis), and cleaved was investigated by immunofluorescence analysis and Western blotting. In this study, we investigated the neuroprotective effect of neuregulin 1 (NRG1) against cytotoxicity induced by APP-CT31. Our data showed that CT31 induced cytotoxicity and apoptosis in SH-SY5Y cells and primary cortical neurons. NRG1 attenuated the neurotoxicity induced by the expression of APP-CT31. We also showed that APP-CT31 altered the expression of p53 and cleaved caspase 3. However, treatment with NRG1 rescued the APP-CT31-induced upregulation of p53 and cleaved caspase 3 expression. The protective effect of NRG1 was abrogated by inhibition of the ErbB4 receptor and Akt. These results indicate an important role of ErbB4/Akt signaling in NRG1-mediated neuroprotection, suggesting that endogenous NRG1/ErbB4 signaling represents a valuable therapeutic target in AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是神经元和突触丧失。淀粉样前体蛋白（APP）的细胞质尾巴在特定的细胞内半胱天冬酶位点经历连续切割，产生细胞质末端 31（CT31）片段。APP-CT31 片段是凋亡的有效诱导剂。通过乳酸脱氢酶（LDH）测定评估 APP-CT31 在 SH-SY5Y 细胞中的细胞毒性。TUNEL 染色用于检测 SH-SY5Y 细胞和原代皮质神经元中的凋亡信号。通过免疫荧光分析和 Western blot 研究凋亡相关蛋白（如 p53、PUMA（p53 上调凋亡调节剂）和 cleaved）的表达。在这项研究中，我们研究了神经调节蛋白 1（NRG1）对 APP-CT31 诱导的细胞毒性的神经保护作用。我们的数据表明，CT31 诱导 SH-SY5Y 细胞和原代皮质神经元的细胞毒性和凋亡。NRG1 减轻了 APP-CT31 表达诱导的神经毒性。我们还表明，APP-CT31 改变了 p53 和 cleaved caspase 3 的表达。然而，用 NRG1 处理可挽救 APP-CT31 诱导的 p53 和 cleaved caspase 3 表达上调。NRG1 的保护作用被 ErbB4 受体和 Akt 的抑制所阻断。这些结果表明 ErbB4/Akt 信号在 NRG1 介导的神经保护中起重要作用，表明内源性 NRG1/ErbB4 信号代表 AD 的有价值的治疗靶点。
