2. Academic Validation
  3. RA-PR058, a novel ramalin derivative, reduces BACE1 expression and phosphorylation of tau in Alzheimer's disease mouse models

RA-PR058, a novel ramalin derivative, reduces BACE1 expression and phosphorylation of tau in Alzheimer's disease mouse models

  • Anim Cells Syst (Seoul). 2025 Feb 7;29(1):122-134. doi: 10.1080/19768354.2025.2459649.
Yongeun Cho 1,  Jeongmi Lee 1,  Jun-Sik Kim 1,  Yeji Jeon 1,  Sukmin Han 2,  Heewon Cho 1,  Yeongyeong Lee 1,  Tai Kyoung Kim 3,  Ju-Mi Hong 3,  Yujeong Lee 1,  Yujung Byun 1,  Minshik Chae 1,  Sunyoung Park 1,  Leon F Palomera 1,  Sang Yoon Park 4,  Hyunwook Kim 4,  Soyeong Kim 5,  Seongeun Kang 5,  Jun-Goo Jee 6,  Hongchan An 5 7,  Joung Han Yim 3,  Sung Hyun Kim 2 8,  Dong-Gyu Jo 1 9 10 11
Affiliations

Affiliations

  • 1 School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
  • 2 Department of Neuroscience, Graduate School, Kyung Hee University, Seoul, Republic of Korea.
  • 3 Division of Polar Life Sciences, Korea Polar Research Institute, Incheon, Republic of Korea.
  • 4 Bio Research Dept., Ahngook Pharmaceutical, Gwacheon, Republic of Korea.
  • 5 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, Republic of Korea.
  • 6 College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.
  • 7 College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Republic of Korea.
  • 8 Department of Physiology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
  • 9 Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
  • 10 Biomedical Institute for Convergence, Sungkyunkwan University, Suwon, Republic of Korea.
  • 11 Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Republic of Korea.
PMID: 39931645 DOI: 10.1080/19768354.2025.2459649
Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the Enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated in vitro and in vivo. In vitro studies used SH-SY5Y cells under oxidative stress conditions to assess BACE1 expression, while in vivo effects were studied in 3xTg-AD mice following one month of oral RA-PR058 treatment. Behavioral assessments, biochemical analyses, transcriptomic profiling, and pharmacokinetic evaluations were performed to determine the efficacy of RA-PR058. RA-PR058 significantly reduced oxidative stress-induced BACE1 expression in vitro and decreased cortical BACE1 expression in 3xTg-AD mice. In vivo treatment alleviated anxiety-like behavior and reduced tau phosphorylation at disease-relevant sites (Ser202/Thr205, Thr231, and Ser396). Transcriptomic analysis revealed RA-PR058-mediated gene expression changes related to central nervous system development, response to hypoxia, and neuroactive ligand-receptor interactions, suggesting broader regulatory effects on AD-related pathways. Pharmacokinetic analysis demonstrated that RA-PR058 exhibits high metabolic stability, minimal Cytochrome P450 interactions, and moderate blood-brain barrier penetration. RA-PR058 demonstrates potential as a multi-target AD therapeutic by reducing BACE1 expression, tau hyperphosphorylation, and anxiety-like behavior, coupled with favorable pharmacokinetics. Additional studies are needed to assess cognitive effects and clarify molecular mechanisms, but RA-PR058 may represent a promising advancement in addressing AD's complex pathology.

Keywords

Alzheimer’s disease; BACE1; RA-PR058; Tau.

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