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Adv. Sci., Jan 04 2025, | https://doi.org/10.1002/advs.202407812 A Novel RAGE Modulator Induces Soluble RAGE to Reduce BACE1 Expression in Alzheimer's Disease

Seung-Hyun Baek ¹, Suji Hong ¹, Eunae Kim ¹, Sunyoung Park ¹, Minyoung Lee², Jinsu Park ¹, Yoonsuk Cho ¹, Hyunjun Yoon ³, Daeseung Kim ³, Youngkwang Yun¹, Youbin Kim⁴, Yoonjung Choi ³, Keunsoo Kang ^3,5, Sangyong Jung ⁶, Jun Pyo Kim ⁷, Eunha Kim², Sang Won Seo ^7,8,9, Yong-Keun Jung ⁴, Dong-Gyu Jo ^1,10,11,12

¹School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
²Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea.
³Deargen Inc., Daejeon, 34051, Republic of Korea.
⁴School of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
⁵Department of Microbiology, College of Science and Technology, Dankook University, Cheonan, 31116, Republic of Korea.
⁶Department of Medical Science, College of Medicine, CHA University, Seongnam, 13496, Republic of Korea.
⁷Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06355, Republic of Korea.
⁸Alzheimer's Disease Convergence Research Center, Samsung Medical Center, Seoul, 06351, Republic of Korea.
⁹Neuroscience Center, Samsung Medical Center, Seoul, 06351, Republic of Korea.
¹⁰Biomedical Institute for Convergence at SKKU (BICS), Suwon, 16419, Republic of Korea.
¹¹Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06355, Republic of Korea.
¹²Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

Corresponding Author : Dong-Gyu Jo

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.

논문정보

형식Research article
게재일2025년 01월 (BRIC 등록일 2025-01-06)
연구진국내 연구진
분야 의약학 > 신경의학

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