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

IF 14.3 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
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
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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.

Abstract Image

一种新的RAGE调节剂诱导可溶性RAGE降低阿尔茨海默病中BACE1的表达
β-分泌酶(BACE1)在淀粉样蛋白-β (Aβ)的产生中起着重要作用,在阿尔茨海默病(AD)神经病理学中存在过表达。Aβ与晚期糖基化终产物受体(RAGE)的相互作用促进了Aβ的大脑摄取,并加剧了其神经毒性和神经炎症,进一步增加了BACE1的表达。鉴于先前BACE1抑制努力的局限性,本研究探索降低BACE1表达以减轻AD病理。研究表明,抗癌药物6-硫代鸟苷(6-TG)在不引起细胞毒性的情况下显著降低BACE1的表达,同时增强小胶质细胞的吞噬活性,并通过减少Aβ积累改善AD小鼠的认知障碍。利用先进的基于深度学习的靶标识别工具,并与表面等离子体共振实验相证实,研究人员阐明了6-TG直接与RAGE相互作用,通过JAK2-STAT1途径调节BACE1的表达,并提高大脑中可溶性RAGE (sRAGE)水平。这些发现阐明了6-TG在改善阿尔茨海默病表现方面的治疗潜力,并倡导采用小分子策略来提高大脑sRAGE水平,为阿尔茨海默病的复杂性带来的挑战提供了一种战略选择。
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来源期刊
Advanced Science
Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
18.90
自引率
2.60%
发文量
1602
审稿时长
1.9 months
期刊介绍: Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.
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