Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1.
Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1.
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KLK8的上调通过裂解NCAM1参与了CUMS诱导的海马神经元凋亡。
DOI：
10.1038/s41419-023-05800-5
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发表时间：
2023-04-19
影响因子：
9
通讯作者：
Liu, Yu-Jian
中科院分区：
文献类型：
--
作者：
Xu, Dan-Hong;Du, Jian-Kui;Liu, Shi-Yu;Zhang, Hui;Yang, Lu;Zhu, Xiao-Yan;Liu, Yu-Jian
神经元凋亡已被公认为抑郁症发病机制中的关键介质。组织激肽释放酶相关肽酶8（KLK 8）是一种胰蛋白酶样丝氨酸蛋白酶，与几种精神疾病的发病机制有关。本研究旨在探讨KLK 8在慢性不可预测的轻度应激（CHMS）诱导的抑郁症模型中与抑郁症相关的海马神经元细胞凋亡中的潜在功能。研究发现，在CNS诱导的小鼠中，抑郁样行为与海马KLK 8上调相关。KLK 8的转基因过表达加剧，而KLK 8缺陷减弱了CNS诱导的抑郁样行为和海马神经元凋亡。在HT 22小鼠海马神经元细胞和原代海马神经元中，腺病毒介导的KLK 8过表达（Ad-KLK 8）足以诱导神经元凋亡。从机制上讲，由于KLK 8蛋白水解切割NCAM 1细胞外结构域，因此确定神经细胞粘附分子1（NCAM 1）可能与海马神经元中的KLK 8结合。免疫荧光染色显示NCAM 1在海马切片中减少，这些海马切片来自暴露于COMS的小鼠或大鼠。KLK 8的转基因过表达加剧，而KLK 8缺陷在很大程度上阻止了海马中CNS诱导的NCAM 1丢失。腺病毒介导的NCAM 1和NCAM 1模拟肽的过表达均可拯救KLK 8过表达的神经元细胞免于凋亡。总的来说，这项研究确定了一个新的促凋亡机制，在海马中的发病过程中，通过上调KLK 8诱导的抑郁症，并提出了KLK 8作为抑郁症的潜在治疗靶点的可能性。
Neuronal apoptosis has been well-recognized as a critical mediator in the pathogenesis of depressive disorders. Tissue kallikrein-related peptidase 8 (KLK8), a trypsin-like serine protease, has been implicated in the pathogenesis of several psychiatric disorders. The present study aimed to explore the potential function of KLK8 in hippocampal neuronal cell apoptosis associated with depressive disorders in rodent models of chronic unpredictable mild stress (CUMS)-induced depression. It was found that depression-like behavior in CUMS-induced mice was associated with hippocampal KLK8 upregulation. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency attenuated CUMS-induced depression-like behaviors and hippocampal neuronal apoptosis. In HT22 murine hippocampal neuronal cells and primary hippocampal neurons, adenovirus-mediated overexpression of KLK8 (Ad-KLK8) was sufficient to induce neuron apoptosis. Mechanistically, it was identified that the neural cell adhesion molecule 1 (NCAM1) may associate with KLK8 in hippocampal neurons as KLK8 proteolytically cleaved the NCAM1 extracellular domain. Immunofluorescent staining exhibited decreased NCAM1 in hippocampal sections obtained from mice or rats exposed to CUMS. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency largely prevented CUMS-induced loss of NCAM1 in the hippocampus. Both adenovirus-mediated overexpression of NCAM1 and NCAM1 mimetic peptide rescued KLK8-overexpressed neuron cells from apoptosis. Collectively, this study identified a new pro-apoptotic mechanism in the hippocampus during the pathogenesis of CUMS-induced depression via the upregulation of KLK8, and raised the possibility of KLK8 as a potential therapeutic target for depression.
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影响因子：
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作者：
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通讯作者：
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