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一种新型晚期糖基化终末产物受体调节剂可诱导可溶性晚期糖基化终末产物受体以降低阿尔茨海默病中β-分泌酶1的表达。

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

作者信息

Baek Seung-Hyun, Hong Suji, Kim Eunae, Park Sunyoung, Lee Minyoung, Park Jinsu, Cho Yoonsuk, Yoon Hyunjun, Kim Daeseung, Yun Youngkwang, Kim Youbin, Choi Yoonjung, Kang Keunsoo, Jung Sangyong, Kim Jun Pyo, Kim Eunha, Seo Sang Won, Jung Yong-Keun, Jo Dong-Gyu

机构信息

School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea.

出版信息

Adv Sci (Weinh). 2025 Feb;12(8):e2407812. doi: 10.1002/advs.202407812. Epub 2025 Jan 4.

DOI:10.1002/advs.202407812
PMID:39755927
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11848596/
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.

摘要

β-分泌酶（BACE1）在淀粉样β蛋白（Aβ）的产生过程中起重要作用，在阿尔茨海默病（AD）神经病理学中存在过表达现象。Aβ与晚期糖基化终产物受体（RAGE）的相互作用促进了大脑对Aβ的摄取，并加剧了其神经毒性和神经炎症，进而进一步增加了BACE1的表达。鉴于先前抑制BACE1的努力存在局限性，该研究探索降低BACE1表达以减轻AD病理学变化。研究发现，抗癌药物6-硫鸟嘌呤（6-TG）能显著降低BACE1的表达，且不会引发细胞毒性，同时增强小胶质细胞的吞噬活性，并改善AD小鼠的认知障碍，减少Aβ的积累。利用先进的基于深度学习的工具进行靶点识别，并通过表面等离子体共振测定法进行验证，结果表明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）的水平。这些发现揭示了6-TG在改善AD表现方面的治疗潜力，并提倡采用小分子策略来提高大脑中sRAGE的水平，为应对AD复杂性带来的挑战提供了一种战略选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/65c356fa9f5e/ADVS-12-2407812-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/766f20cc733c/ADVS-12-2407812-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/e74912cf48cb/ADVS-12-2407812-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/e0584fef231d/ADVS-12-2407812-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/f072774a2805/ADVS-12-2407812-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/3675acc20abb/ADVS-12-2407812-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/a29d8b480f9e/ADVS-12-2407812-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/65c356fa9f5e/ADVS-12-2407812-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/766f20cc733c/ADVS-12-2407812-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/e74912cf48cb/ADVS-12-2407812-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/e0584fef231d/ADVS-12-2407812-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/f072774a2805/ADVS-12-2407812-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/3675acc20abb/ADVS-12-2407812-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/a29d8b480f9e/ADVS-12-2407812-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65c3/11848596/65c356fa9f5e/ADVS-12-2407812-g003.jpg

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