Park Moonsu, Ryu Hongji, Heo Suyeon, Kim Boyoung, Park Junhang, Lim Key-Hwan, Han Sang-Bae, Park Hanseul
Laboratory of Molecular Genetics, College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea.
College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea.
Theranostics. 2025 Jan 1;15(2):428-438. doi: 10.7150/thno.103455. eCollection 2025.
Cathepsin D (Ctsd) has emerged as a promising therapeutic target for Alzheimer's disease (AD) due to its role in degrading intracellular amyloid beta (Aβ). Enhancing Ctsd activity could reduce Aβ42 accumulation and restore the Aβ42/40 ratio, offering a potential AD treatment strategy. This study explored Ctsd demethylation in AD mouse models using dCas9-Tet1-mediated epigenome editing. We identified dCas9-Tet1 as an effective tool for demethylating the endogenous Ctsd gene in primary neurons and brains. Treatment with Ctsd-targeted dCas9-Tet1 in primary neurons overexpressing mutant APP (mutAPP) reduced Aβ peptide levels and the Aβ42/40 ratio. Additionally, demethylation of Ctsd via dCas9-Tet1 in 5xFAD mice significantly altered Aβ levels and alleviated cognitive and behavioral deficits. These findings offer valuable insights into developing epigenome editing-based gene therapy strategies for AD.
组织蛋白酶D（Ctsd）因其在降解细胞内β淀粉样蛋白（Aβ）中的作用，已成为治疗阿尔茨海默病（AD）的一个有前景的治疗靶点。增强Ctsd活性可减少Aβ42积累并恢复Aβ42/40比值，提供了一种潜在的AD治疗策略。本研究利用dCas9-Tet1介导的表观基因组编辑，在AD小鼠模型中探索Ctsd去甲基化。我们确定dCas9-Tet1是一种在原代神经元和大脑中使内源性Ctsd基因去甲基化的有效工具。在过表达突变型APP（mutAPP）的原代神经元中，用靶向Ctsd的dCas9-Tet1处理可降低Aβ肽水平和Aβ42/40比值。此外，在5xFAD小鼠中通过dCas9-Tet1使Ctsd去甲基化，显著改变了Aβ水平，并减轻了认知和行为缺陷。这些发现为开发基于表观基因组编辑的AD基因治疗策略提供了有价值的见解。
