Zheng Naizhen, Li Kun, Cao Jing, Wang Zijie, Zhang Liang, Zhao Zihao, He Jiawei, Wang Yong, Zhu Xiang, Chen Yiqing, Meng Jian, Zhao Dongdong, Niu Mengxi, Luo Hong, Zhang Xian, Sun Hao, Zhang Yun-Wu
Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, and Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
Transl Psychiatry. 2025 Jan 10;15(1):5. doi: 10.1038/s41398-025-03227-4.
Long-term potentiation (LTP) and long-term depression (LTD) are widely used to study synaptic plasticity. However, whether proteins regulating LTP and LTD are altered in cognitive disorders and contribute to disease onset remains to be determined. Herein, we induced LTP and LTD in the hippocampal CA3-CA1 Schaffer collateral pathway, respectively, and then performed proteomic analysis of the CA1 region. We identified 20 differentially expressed proteins (DEPs) shared by the LTP and the LTD processes. Among them, we found that HtrA serine peptidase 2 (HTRA2) was mainly expressed in neurons and that HTRA2 levels were increased in both the LTP and the LTD processes in C57BL/6 mice. HTRA2 downregulation impaired synapses and reduced ATP production in cultured primary neurons. Furthermore, adeno-associated virus (AAV)-mediated HTRA2 downregulation in the hippocampus impaired synaptic plasticity and cognitive function in C57BL/6 mice. Moreover, we found that HTRA2 expression decreased in the brains of Alzheimer's disease patients, frontotemporal lobar degeneration with ubiquitin inclusions patients, and tauopathy model mice. Finally, we showed that lentivirus-mediated HTRA2 overexpression in the hippocampus rescued PP2B reduction, alleviated tau hyperphosphorylation, and partially attenuated synaptic plasticity and cognitive deficits in the PS19 tauopathy model mice. Our study not only indicates that HTRA2 in neurons plays an important role in regulating synaptic plasticity under both physiological and pathological conditions, but also provides a novel, electrophysiology-based strategy to identify proteins regulating synaptic plasticity systematically.
长时程增强（LTP）和长时程抑制（LTD）被广泛用于研究突触可塑性。然而，调节LTP和LTD的蛋白质在认知障碍中是否发生改变并导致疾病发生仍有待确定。在此，我们分别在海马CA3-CA1 谢弗侧支通路中诱导LTP和LTD，然后对CA1区域进行蛋白质组学分析。我们鉴定出LTP和LTD过程共有的20种差异表达蛋白（DEP）。其中，我们发现丝氨酸蛋白酶2（HTRA2）主要在神经元中表达，并且在C57BL/6小鼠的LTP和LTD过程中HTRA2水平均升高。HTRA2下调会损害培养的原代神经元中的突触并减少ATP生成。此外，腺相关病毒（AAV）介导的海马中HTRA2下调会损害C57BL/6小鼠的突触可塑性和认知功能。此外，我们发现阿尔茨海默病患者、伴有泛素包涵体的额颞叶变性患者以及tau蛋白病模型小鼠大脑中的HTRA2表达降低。最后，我们表明慢病毒介导的海马中HTRA2过表达可挽救PP2B减少，减轻tau蛋白过度磷酸化，并部分减轻PS19 tau蛋白病模型小鼠的突触可塑性和认知缺陷。我们的研究不仅表明神经元中的HTRA2在生理和病理条件下调节突触可塑性中起重要作用，还提供了一种基于电生理学的新策略来系统地鉴定调节突触可塑性的蛋白质。
