Targeted demethylation of cathepsin D via epigenome editing rescues pathology in Alzheimer's disease mouse model
Moonsu Park, Hongji Ryu, Suyeon Heo, Bo Young Kim, Junhang Park, Key‐Hwan Lim, Sang-Bae Han, Hanseul Park
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 (A).Enhancing Ctsd activity could reduce A42 accumulation and restore the A42/40 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 A peptide levels and the A42/40 ratio.Additionally, in vivo demethylation of Ctsd via dCas9-Tet1 in 5xFAD mice significantly altered A levels and alleviated cognitive and behavioral deficits. Conclusion:These findings offer valuable insights into developing epigenome editing-based gene therapy strategies for AD.