通过表观基因组编辑靶向组织蛋白酶D去甲基化可挽救阿尔茨海默病小鼠模型的病理。

IF 12.4 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Theranostics Pub Date : 2025-01-01 DOI:10.7150/thno.103455

Moonsu Park, Hongji Ryu, Suyeon Heo, Boyoung Kim, Junhang Park, Key-Hwan Lim, Sang-Bae Han, Hanseul Park

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引用次数: 0

摘要

背景：组织蛋白酶D （Ctsd）由于其降解细胞内β淀粉样蛋白（a β）的作用而成为阿尔茨海默病（AD）的一个有希望的治疗靶点。增强Ctsd活性可减少a β42积累，恢复a β42/40比值，为AD的治疗提供了潜在的策略。方法：利用dcas9 - tet1介导的表观基因组编辑技术，研究AD小鼠模型中Ctsd的去甲基化。我们发现dCas9-Tet1是一个有效的工具去甲基化内源性Ctsd基因在初级神经元和活体大脑。结果：ctsd靶向dCas9-Tet1处理过表达突变体APP （mutAPP）的原代神经元，可降低Aβ肽水平和Aβ42/40比值。此外，5xFAD小鼠体内通过dCas9-Tet1对Ctsd进行去甲基化，显著改变了Aβ水平，减轻了认知和行为缺陷。结论：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。

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Targeted demethylation of cathepsin D via epigenome editing rescues pathology in Alzheimer's disease mouse model.

Background: 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. Methods: 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 in vivo brains. Results: Treatment with Ctsd-targeted dCas9-Tet1 in primary neurons overexpressing mutant APP (mutAPP) reduced Aβ peptide levels and the Aβ42/40 ratio. Additionally, in vivo demethylation of Ctsd via dCas9-Tet1 in 5xFAD mice significantly altered Aβ levels and alleviated cognitive and behavioral deficits. Conclusion: These findings offer valuable insights into developing epigenome editing-based gene therapy strategies for AD.

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来源期刊

Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

25.40

自引率

1.60%

发文量

433

审稿时长

1 months

期刊介绍： Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.