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

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. © 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

Citation

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. A Novel RAGE Modulator Induces Soluble RAGE to Reduce BACE1 Expression in Alzheimer's Disease. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2025 Feb;12(8):e2407812

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PMID: 39755927

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