| First Author | Park M | Year | 2025 |
| Journal | Theranostics | Volume | 15 |
| Issue | 2 | Pages | 428-438 |
| PubMed ID | 39744681 | Mgi Jnum | J:361237 |
| Mgi Id | MGI:7798571 | Doi | 10.7150/thno.103455 |
| Citation | Park M, et al. (2025) Targeted demethylation of cathepsin D via epigenome editing rescues pathology in Alzheimer's disease mouse model. Theranostics 15(2):428-438 |
| abstractText | 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 (Abeta). Enhancing Ctsd activity could reduce Abeta42 accumulation and restore the Abeta42/40 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 Abeta peptide levels and the Abeta42/40 ratio. Additionally, in vivo demethylation of Ctsd via dCas9-Tet1 in 5xFAD mice significantly altered Abeta levels and alleviated cognitive and behavioral deficits. Conclusion: These findings offer valuable insights into developing epigenome editing-based gene therapy strategies for AD. |
