Journal Article

ELK1 inhibition alleviates amyloid pathology and memory decline by promoting the SYVN1-mediated ubiquitination and degradation of PS1 in Alzheimer’s disease

Yi, Lilin, He, Yan, Fan, Yepeng, He, Guiqiong, Wang, Maoju, Xu, Mingliang, Tian, Qiuyun, Li, Junjie, Du, Yehong, Wang, Jiaojiao, Wu, Bin, Luo, Man, Dong, Zhifang, Xia, Lei, Guo, Song, Chen, Mulan, Xu, Boqing, Song, Weihong

2025

Overview

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 elevation linked to Alzheimer’s disease athology Alzheimer’s disease is a leading cause of memory impairment in older adults. Researchers found that ELK1 levels are higher in patients with Alzheimer’s disease and animal models. Through genetic and drug methods to suppress ELK1 activity, they observed reduced accumulation of pathogenic proteins and improved memory in mice. This study employs a comprehensive approach involving human and murine brain tissues analysis, as well as cell cultures. The investigation specifically examined the regulatory effects of ELK1 on PS1, a protein implicated in the production of neurotoxic amyloid plaques. They discovered that ELK1 inhibits PS1 degradation, leading to more plaque formation. By suppressing ELK1 activity, they observed a decrease in plaque formation and improvements in memory tests for mice. This suggests that targeting ELK1 could be a potential treatment strategy for Alzheimer’s disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/109 / 13/51 / 14/19 / 38/1 / 38/109 / 38/23 / 631/337/458/582 / 631/378/1595/1554 / 64/110 / 82/29 / 9/74 / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid / Amyloid beta-Peptides - metabolism / Amyloidogenesis / Animal models / Animals / Artificial intelligence / Biomedical and Life Sciences / Biomedicine / Brain - metabolism / Brain - pathology / Degradation / Disease Models, Animal / ets-Domain Protein Elk-1 - antagonists & inhibitors / ets-Domain Protein Elk-1 - genetics / ets-Domain Protein Elk-1 - metabolism / Extracellular signal-regulated kinase / Humans / Immunological memory / Kinases / Male / Medical Biochemistry / Memory / Memory Disorders - etiology / Memory Disorders - metabolism / Memory Disorders - pathology / Mice / Mice, Transgenic / Molecular Medicine / Neurodegenerative diseases / Neuropathogenesis / Neurotoxicity / Pathogenesis / Pathology / Phosphorylation / Presenilin 1 / Presenilin-1 - metabolism / Proteolysis / Senile plaques / Stem Cells / Tissues / Transcription factors / Transgenic mice / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - metabolism / Ubiquitination / β-Amyloid / 생화학