当前位置: X-MOL 学术Transl. Psychiaty › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Neurotrophic factor-α1, a novel tropin is critical for the prevention of stress-induced hippocampal CA3 cell death and cognitive dysfunction in mice: comparison to BDNF
Translational Psychiatry ( IF 6.8 ) Pub Date : 2021-01-07 , DOI: 10.1038/s41398-020-01112-w
Lan Xiao 1 , Vinay Kumar Sharma 1 , Leila Toulabi 1 , Xuyu Yang 1 , Cheol Lee 1 , Daniel Abebe 1 , Areg Peltekian 1 , Irina Arnaoutova 1 , Hong Lou 1 , Y Peng Loh 1
Affiliation  

Stress leads to brain pathology including hippocampal degeneration, cognitive dysfunction, and potential mood disorders. Hippocampal CA3, a most stress-vulnerable region, consists of pyramidal neurons that regulate cognitive functions e.g. learning and memory. These CA3 neurons express high levels of the neuroprotective protein, neurotrophic factor-α1 (NF-α1), also known as carboxypeptidase E (CPE), and receive contacts from granule cell projections that release BDNF which has neuroprotective activity. Whether NF-α1-CPE and/or BDNF are critical in protecting these CA3 neurons against severe stress-induced cell death is unknown. Here we show that social combined with the physical stress of maternal separation, ear tagging, and tail snipping at weaning in 3-week-old mice lacking NF-α1-CPE, led to complete hippocampal CA3 degeneration, despite having BDNF and active phosphorylated TrkB receptor levels similar to WT animals. Mice administered TrkB inhibitor, ANA12 which blocked TrkB phosphorylation showed no degeneration of the CA3 neurons after the weaning stress paradigm. Furthermore, transgenic knock-in mice expressing CPE-E342Q, an enzymatically inactive form, replacing NF-α1-CPE, showed no CA3 degeneration and exhibited normal learning and memory after the weaning stress, unlike NF-α1-CPE-KO mice. Mechanistically, we showed that radio-labeled NF-α1-CPE bound HT22 hippocampal cells in a saturable manner and with high affinity (Kd = 4.37 nM). Subsequently, treatment of the HT22cpe−/− cells with NF-α1-CPE or CPE-E342Q equivalently activated ERK signaling and increased BCL2 expression to protect these neurons against H2O2-or glutamate-induced cytotoxicity. Our findings show that NF-α1-CPE is more critical compared to BDNF in protecting CA3 pyramidal neurons against stress-induced cell death and cognitive dysfunction, independent of its enzymatic activity.



中文翻译:

神经营养因子-α1,一种新的肌钙蛋白对于预防小鼠应激诱导的海马 CA3 细胞死亡和认知功能障碍至关重要:与 BDNF 的比较

压力会导致脑部病变,包括海马退化、认知功能障碍和潜在的情绪障碍。海马 CA3 是最易受压力影响的区域,由调节认知功能(例如学习和记忆)的锥体神经元组成。这些 CA3 神经元表达高水平的神经保护蛋白、神经营养因子-α1 (NF-α1),也称为羧肽酶 E (CPE),并与释放具有神经保护活性的 BDNF 的颗粒细胞投射接触。NF-α1-CPE 和/或 BDNF 在保护这些 CA3 神经元免受严重应激诱导的细胞死亡方面是否至关重要尚不清楚。在这里,我们表明缺乏 NF-α1-CPE 的 3 周龄小鼠在断奶时与母体分离、耳朵标记和剪尾等身体压力相结合,导致海马 CA3 完全变性,尽管具有与 WT 动物相似的 BDNF 和活性磷酸化 TrkB 受体水平。给予阻断 TrkB 磷酸化的 TrkB 抑制剂 ANA12 的小鼠在断奶应激范式后显示 CA3 神经元没有退化。此外,与 NF-α1-CPE-KO 小鼠不同,表达 CPE-E342Q(一种酶失活形式,替代 NF-α1-CPE)的转基因敲入小鼠在断奶应激后没有显示 CA3 变性,并且表现出正常的学习和记忆。从机制上讲,我们发现放射性标记的 NF-α1-CPE 以可饱和的方式和高亲和力(Kd = 4.37 nM)结合 HT22 海马细胞。随后,对 HT22 进行处理 阻断 TrkB 磷酸化的 ANA12 在断奶压力范式后显示 CA3 神经元没有退化。此外,与 NF-α1-CPE-KO 小鼠不同,表达 CPE-E342Q(一种酶失活形式,替代 NF-α1-CPE)的转基因敲入小鼠在断奶应激后没有显示 CA3 变性,并且表现出正常的学习和记忆。从机制上讲,我们发现放射性标记的 NF-α1-CPE 以可饱和的方式和高亲和力(Kd = 4.37 nM)结合 HT22 海马细胞。随后,对 HT22 进行处理 阻断 TrkB 磷酸化的 ANA12 在断奶压力范式后显示 CA3 神经元没有退化。此外,与 NF-α1-CPE-KO 小鼠不同,表达 CPE-E342Q(一种酶失活形式,替代 NF-α1-CPE)的转基因敲入小鼠在断奶应激后没有显示 CA3 变性,并且表现出正常的学习和记忆。从机制上讲,我们发现放射性标记的 NF-α1-CPE 以可饱和的方式和高亲和力(Kd = 4.37 nM)结合 HT22 海马细胞。随后,对 HT22 进行处理 我们发现放射性标记的 NF-α1-CPE 以饱和方式和高亲和力 (Kd = 4.37 nM) 结合 HT22 海马细胞。随后,对 HT22 进行处理 我们发现放射性标记的 NF-α1-CPE 以饱和方式和高亲和力 (Kd = 4.37 nM) 结合 HT22 海马细胞。随后,对 HT22 进行处理具有 NF-α1-CPE 或 CPE-E342Q 的cpe-/-细胞等效地激活 ERK 信号并增加 BCL2 表达以保护这些神经元免受 H 2 O 2 - 或谷氨酸诱导的细胞毒性。我们的研究结果表明,与 BDNF 相比,NF-α1-CPE 在保护 CA3 锥体神经元免受应激诱导的细胞死亡和认知功能障碍方面更为重要,与其酶活性无关。

更新日期:2021-01-07
down
wechat
bug