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

Theranostics. 2025 Jan 1;15(2):428-438. doi: 10.7150/thno.103455. eCollection 2025.

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.

Keywords: Alzheimer's disease; CRISPR/dCas9-Tet1; cathepsin D; epigenome editing; in vivo gene editing.

MeSH terms

  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / therapy
  • Amyloid beta-Peptides* / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • CRISPR-Cas Systems / genetics
  • Cathepsin D* / genetics
  • Cathepsin D* / metabolism
  • Disease Models, Animal*
  • Epigenome*
  • Gene Editing* / methods
  • Genetic Therapy / methods
  • Humans
  • Male
  • Mice
  • Mice, Transgenic*
  • Neurons / metabolism

Substances

  • Amyloid beta-Peptides
  • Cathepsin D
  • Amyloid beta-Protein Precursor