Int J Biol Macromol. 2025 Nov 17:149074. doi: 10.1016/j.ijbiomac.2025.149074. Online ahead of print.
ABSTRACT
Alzheimer’s disease (AD) is a common neurodegenerative disorder among the elderly. Our recent research revealed that increased ELK1 (E-twenty-six (ETS)-like protein 1) in AD competitively binds to the C-terminal fragment of presenilin-1 (PS1-CTF), thereby inhibiting E3 ubiquitin ligase synoviolin (SYVN1)-mediated ubiquitination and degradation of PS1, ultimately aggravating pathological progression. However, the precise molecular interface of this interaction and the therapeutic potential of its targeted disruption remain unknown. In the present study, we identified the critical ELK1-binding epitope within PS1 (amino acids 408-429) and, based on this discovery, developed Tat-PS1408-429, a cell-penetrating peptide containing this sequence that specifically disrupts pathological PS1-ELK1 interaction. Tat-PS1408-429 competitively bound to ELK1, attenuating its interaction with PS1 and promoting SYVN1-mediated PS1 degradation. Importantly, disruption of the PS1-ELK1 interaction with Tat-PS1408-429 substantially diminished amyloidogenic processing of amyloid-β (Aβ) precursor protein (APP), leading to reduced Aβ accumulation and improved cognitive and synaptic function in APP23/PS45 double transgenic AD model mice. Collectively, these findings demonstrate that ELK1 interacts with the PS1408-429 domain and disruption of this interaction by Tat-PS1408-429 can alleviate AD-related neuropathology and memory deficits, highlighting its potential as a promising therapeutic peptide for AD.
PMID:41260424 | DOI:10.1016/j.ijbiomac.2025.149074
