Yi Lilin, Li Junjie, He Yan, Wang Jiaojiao, Wang Maoju, Guo Song, Luo Man, Wu Bin, Xu Mingliang, Tian Qiuyun, Fan Yepeng, Chen Mulan, Xu Boqing, Xia Lei, Song Weihong, He Guiqiong, Du Yehong, Dong Zhifang
Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
Exp Mol Med. 2025 May 1. doi: 10.1038/s12276-025-01455-8.
ELK1 is a member of the E-twenty-six transcription factor family and is usually activated by phosphorylation at Ser383 and Ser389 by extracellular signal-regulated kinase 1/2 (ERK1/2). Dysregulation of ERK1/2 is involved in Alzheimer's disease (AD)-related neuropathogenesis and cognitive impairments. However, the role of ELK1 in AD pathogenesis remains unclear. Here we report that the expression of ELK1 was significantly increased in the brain tissues of patients with AD and AD model mice. The genetic knockdown of ELK1 or inhibition of its phosphorylation by an interfering peptide (TAT-DEF-ELK1 (TDE)) reduced amyloidogenic processing of APP by targeting PS1, consequently inhibiting Aβ generation and alleviating synaptic and memory impairments in APP23/PS45 double-transgenic AD model mice. In addition, we further found that ELK1 regulated the expression of PS1 by competitively inhibiting the interaction between PS1 and its E3 ubiquitin ligase synoviolin (SYVN1), thereby inhibiting the SYVN1-mediated ubiquitination and degradation of PS1. Our results demonstrate that ELK1 aberrantly increases in AD and genetic or pharmacological inhibition of ELK1 can alleviate AD-related pathology and memory impairments by enhancing the SYVN1-mediated PS1 ubiquitination and degradation, indicating that ELK1 may be a novel target for AD treatment.
ELK1是E-26转录因子家族的成员，通常通过细胞外信号调节激酶1/2（ERK1/2）在Ser383和Ser389位点的磷酸化而被激活。ERK1/2的失调与阿尔茨海默病（AD）相关的神经病理发生和认知障碍有关。然而，ELK1在AD发病机制中的作用仍不清楚。在此我们报告，ELK1的表达在AD患者和AD模型小鼠的脑组织中显著增加。通过干扰肽（TAT-DEF-ELK1（TDE））对ELK1进行基因敲低或抑制其磷酸化，可通过靶向早老素1（PS1）减少淀粉样前体蛋白（APP）的淀粉样生成过程，从而抑制β淀粉样蛋白（Aβ）的产生，并减轻APP23/PS45双转基因AD模型小鼠的突触和记忆障碍。此外，我们进一步发现，ELK1通过竞争性抑制PS1与其E3泛素连接酶滑膜素（SYVN1）之间的相互作用来调节PS1的表达，从而抑制SYVN1介导的PS1泛素化和降解。我们的结果表明，ELK1在AD中异常增加，对ELK1进行基因或药理学抑制可通过增强SYVN1介导的PS1泛素化和降解来减轻AD相关病理和记忆障碍，这表明ELK1可能是AD治疗的一个新靶点。
