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Theranostics, 2025 Jan 1;15(2):428-438 | https://doi.org/10.7150/thno.103455 Targeted demethylation of cathepsin D via epigenome editing rescues pathology in Alzheimer's disease mouse model

Moonsu Park^1,*, Hongji Ryu^1,*, Suyeon Heo¹, Boyoung Kim¹, Junhang Park¹, Key-Hwan Lim², Sang-Bae Han², Hanseul Park¹

¹Laboratory of Molecular Genetics, College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea.
²College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea.

^*These authors contributed equally: Moonsu Park and Hongji Ryu.
Corresponding author: Hanseul Park, Ph.D.

Abstract

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.

논문정보

형식Research article
게재일2025년 01월 (BRIC 등록일 2025-01-06)
연구진국내 연구진
분야 바이오·의료융합 > 바이오·의료융합 기타

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