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Jan 04, 2025; e2407812.

A Novel RAGE Modulator Induces Soluble RAGE to Reduce BACE1 Expression in Alzheimer's Disease.

Seung-Hyun Baek, Suji Hong, Eunae Kim, Sunyoung Park, Minyoung Lee, Jinsu Park, Yoonsuk Cho, Hyunjun Yoon, Daeseung Kim, Youngkwang Yun, Youbin Kim, Yoonjung Choi, Keunsoo Kang, Sangyong Jung, Jun Pyo Kim, Eunha Kim, Sang Won Seo, Yong-Keun Jung, Dong-Gyu Jo
Author Information
  1. Seung-Hyun Baek: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  2. Suji Hong: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  3. Eunae Kim: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  4. Sunyoung Park: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  5. Minyoung Lee: Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea.
  6. Jinsu Park: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  7. Yoonsuk Cho: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  8. Hyunjun Yoon: Deargen Inc., Daejeon, 34051, Republic of Korea.
  9. Daeseung Kim: Deargen Inc., Daejeon, 34051, Republic of Korea.
  10. Youngkwang Yun: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  11. Youbin Kim: School of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
  12. Yoonjung Choi: Deargen Inc., Daejeon, 34051, Republic of Korea.
  13. Keunsoo Kang: Deargen Inc., Daejeon, 34051, Republic of Korea.
  14. Sangyong Jung: Department of Medical Science, College of Medicine, CHA University, Seongnam, 13496, Republic of Korea.
  15. Jun Pyo Kim: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06355, Republic of Korea.
  16. Eunha Kim: Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea.
  17. Sang Won Seo: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06355, Republic of Korea.
  18. Yong-Keun Jung: School of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
  19. Dong-Gyu Jo: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. ORCID
PMID: 39755927 DOI: 10.1002/advs.202407812

Abstract

β-secretase (BACE1) is instrumental in amyloid-β (Aβ) production, with overexpression noted in Alzheimer's disease (AD) neuropathology. The interaction of Aβ with the receptor for advanced glycation endproducts (RAGE) facilitates cerebral uptake of Aβ and exacerbates its neurotoxicity and neuroinflammation, further augmenting BACE1 expression. Given the limitations of previous BACE1 inhibition efforts, the study explores reducing BACE1 expression to mitigate AD pathology. The research reveals that the anticancer agent 6-thioguanosine (6-TG) markedly diminishes BACE1 expression without eliciting cytotoxicity while enhancing microglial phagocytic activity, and ameliorate cognitive impairments with reducing Aβ accumulation in AD mice. Leveraging advanced deep learning-based tool for target identification, and corroborating with surface plasmon resonance assays, it is elucidated that 6-TG directly interacts with RAGE, modulating BACE1 expression through the JAK2-STAT1 pathway and elevating soluble RAGE (sRAGE) levels in the brain. The findings illuminate the therapeutic potential of 6-TG in ameliorating AD manifestations and advocate for small molecule strategies to increase brain sRAGE levels, offering a strategic alternative to the challenges posed by the complexity of AD.

Keywords

6‐Thioguanosine (6‐TG) Alzheimer's disease (AD) BACE1 RAGE amyloid‐β (Aβ) deep learning drug repurposing

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Grants

  1. NRF-2022R1I1A1A01072791/National Research Foundation of Korea
  2. RS-2019-NR040057/National Research Foundation of Korea
  3. RS-2024-00399237/National Research Foundation of Korea
  4. RS-2024-00345742/National Research Foundation of Korea
  5. RS-2021-KS211513/Ministry of Oceans and Fisheries' R&D project, Korea
  6. No. SMX1240561/Future Medicine 20*30 Project of Samsung Medical Center
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