Traditional Chinese Medicine Targeting the Wnt/β-Catenin Signaling Pathway to Modulate Neuroinflammation in Alzheimer's Disease
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摘要: 在日益严重的老龄化态势下，阿尔茨海默病（Alzheimer's disease，AD）等神经退行性疾病严重危害人口健康。AD以进行性的认知衰退和记忆丧失为主要特征，其发病机制复杂，病程漫长，病理特征包括β-淀粉样蛋白沉积、tau蛋白过度磷酸化、神经炎症反应及氧化应激等多个环节，使得AD的防治面临严峻挑战。目前，针对AD的单抗类靶向药物，不仅疗效有限，且伴随有显著不良反应。相比之下，中药凭借其多成分、多靶点的系统调节优势，在干预AD复杂病理进程，特别是调控神经炎症反应方面展现出独特潜力。本文系统梳理了Wnt/β-catenin信号通路在阿尔茨海默病神经炎症调控中的核心作用，并综述了近年来中药及其活性成分通过干预该通路治疗AD的主要研究进展，旨在为AD的防治提供新的理论依据和策略参考。
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关键词:
- 阿尔茨海默病 /
- Wnt/β-catenin信号通路 /
- 中药 /
- 神经炎症
Abstract: Under the increasingly severe aging demographics, neurodegenerative diseases such as Alzheimer’ s disease （AD） pose serious threats to population health. AD is characterized by progressive cognitive decline and memory loss. Its pathogenic mechanisms are complex, featuring a prolonged disease course and pathological characteristics that encompass multiple aspects, including β-amyloid protein deposition, tau protein hyperphosphorylation, neuroinflammatory responses, and oxidative stress, presenting formidable challenges for AD prevention and treatment. Currently, monoclonal antibody-based targeted therapeutics for AD not only show limited efficacy but are also associated with significant adverse effects. In contrast, traditional Chinese medicine, utilizing its multi-component and multi-target systemic regulatory advantages, exhibits unique potential in intervening in the complex pathological processes of AD, particularly in modulating neuroinflammatory responses. This article systematically reviews the central role of the Wnt/β-catenin signaling pathway in regulating neuroinflammation in Alzheimer's disease and summarizes recent research advances in the treatment of AD by traditional Chinese medicine and its active components through intervention in this pathway, aiming to provide novel theoretical evidence and strategic references for AD prevention and treatment. -
图 1 Wnt/β-catenin 信号通路激活与抑制状态的分子机制（用BioRender 网站自制）
左侧为Wnt信号激活状态：Wnt蛋白与Frizzled受体及LRP共受体结合，抑制胞内破坏复合物活性，β-catenin在胞质中积累并转位入核，与TCF/LEF转录因子结合启动下游靶基因表达。右侧为Wnt信号抑制状态：DKK1结合LRP共受体阻断信号传递，破坏复合物中的GSK-3β磷酸化β-catenin并促使其泛素化降解；核内TCF/LEF与TLE/Groucho共抑制因子结合，抑制靶基因转录。
Figure 1. Molecular mechanisms of Wnt/β-catenin signaling pathway activation and inhibition（Created in BioRender.com）
图 2 中药活性成分激活Wnt/β-catenin通路在AD神经炎症中的核心调控网络（用BioRender 网站自制）
中药活性成分穿透血脑屏障后，通过调控Wnt/β-catenin信号通路，在小胶质细胞（MG）、星形胶质细胞（AS）和神经元三个层面干预AD神经炎症的分子机制。
Figure 2. Core regulatory network of active components of traditional Chinese medicine activating the Wnt/β-catenin pathway in neuroinflammation of Alzheimer's disease
图 3 中药单体及复方调控Wnt/β-catenin通路的机制分类韦恩图
Figure 3. Venn diagram classifying the mechanisms of Chinese medicine monomers and compound formulas in regulating the Wnt/β-catenin signaling pathway
图 4 中药调控Wnt/β-catenin信号通路干预AD的分子机制分类图
根据作用节点的不同，中药及其活性成分对Wnt/β-catenin通路的调控可归纳为三类：（1）上游激活类（绿色）：在配体-受体水平上调Wnt配体或共受体表达。目前尚无中药被证实可直接抑制DKK1。（2）破坏复合物抑制类（黄色）：以胞质GSK-3β为核心靶点，抑制其活性以减少β-catenin降解。（3）下游效应增强类（蓝色）：促进β-catenin核转位并增强TCF/LEF转录活性。图中中药单体/复方带*号者表示其兼有多种机制。
Figure 4. Classification diagram of molecular mechanisms of Chinese herbal medicine regulating Wnt/β-catenin signaling pathway to intervene in AD
图 5 中药靶向Wnt/β-catenin信号通路干预AD的研究证据金字塔
按循证医学证据等级自高而低分为四个层级。Ⅰ级（临床研究）：尚无相关临床试验报道。Ⅱ级（药代动力学与血脑屏障穿透）：现有研究均未系统测定活性成分的脑内暴露量。Ⅲ级（在体动物实验）：已有多项研究采用多种AD转基因及衰老模型验证体内药效。Ⅳ级（体外实验）：已有多项研究在细胞及分子水平验证了中药对通路关键节点的调控作用。现有证据主要集中于Ⅲ级和Ⅳ级，向临床转化的证据链条有待完善。
Figure 5. Evidence pyramid of traditional Chinese medicine targeting Wnt/β-catenin signaling pathway in AD
表 1 中药单体调控Wnt/β-catenin信号通路的主要机制
Table 1. Main mechanisms of Chinese herbal monomers in regulating the Wnt/β-catenin signaling pathway
主要病理机制 药物 作用靶点 在体实验 离体实验 减少tau蛋白磷酸化 葛根素[36] ↓: GSK-3β
↑: β-catenin、cyclin D— SH-SY5Y细胞 西红花苷-1[37] ↓: GSK-3β、p-β-catenin
↑: β-cateninSD大鼠 — 减少tau蛋白磷酸化、Aβ沉积 穿心莲内酯[38] ↑: β-catenin
↓: GSK-3βOctodon degus鼠 — 减少tau蛋白磷酸化、Aβ沉积、减轻神经炎症 大麻二酚[39] ↑: β-catenin、PPARγ
↓: p-GSK-3β、ROS、TNF-α、IL-1β、IL-6— PC12细胞 减少tau蛋白磷酸化、减轻神经炎症、减少细胞凋亡 人参皂苷Rg1[40] ↑: CAT、GSH-PX、SOD1
↓: GSK-3β、β-catenin、Bax、Caspase-3、IL-1、iba-1树鼩 — 减少Aβ沉积、减轻神经炎症、减少细胞凋亡 姜叶多糖[41] ↑: Wnt-3、Lrp-6、β-catenin
↓: GSK-3β、APC、IL-1β、IL-6、TNF-αCL2355线虫 PC12细胞 减少细胞凋亡 姜黄素[42] ↑: p-GSK-3β、β-catenin 、p-Akt、p-CREB
↓: p-β-cateninC57BL/6J 小鼠 — 蛇床子素[43] ↑: β-catenin
↓: GSK-3β— NSCs细胞 淫羊藿苷[44] ↑: β-catenin、HK1、PKM1、PFKM1
↓: GSK-3β、p-β-cateninTg-AD小鼠 HT22细胞 减少Tau磷酸化、减少Aβ沉积、减轻神经炎症 枸杞提取物[45] ↑：Wnt5a/b、KRAS、p-GSK-3β（Ser9）
↓：GSK-3β、Iba1、ROS5×FAD小鼠、
3×TG小鼠— 
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表 2 中药复方调控Wnt/β-catenin信号通路的主要机制
Table 2. Main mechanisms of Chinese hernal compound formulas in regulating the Wnt/β-catenin signaling pathway
主要病理机制 药物 作用靶点 在体实验 离体实验 减少tau蛋白磷酸化、减少Aβ沉积 黄精丸[46]
主要组成：酒黄精、当归↑: Wnt1、DVL2、β-catenin、CyclinD1
↓: GSK-3β昆明小鼠 — 减轻神经炎症、
促进神经元分化黑逍遥散[47]
主要组成：熟地黄、柴胡、当归、白芍、茯苓、白术、生姜、甘草、薄荷↑: β-catenin、PPARγ、IL-10
↓: GSK-3β、TNF-α、IL-6Wistar大鼠 — 减轻神经炎症、抑制细胞凋亡 开心散[48]
主要组成：远志、党参、茯苓、石菖蒲↑: p-GSK-3β、β-catenin、Wnt1、SOD、GSH-Px
↓: GSK-3β、Bax、Caspase-3、
TNF-α、IL-1β、MDA、ROSSD大鼠、APP/PS1小鼠 PC12细胞 减少Aβ沉积、减轻神经炎症 大补阴丸[49]
主要组成：黄柏、知母、熟地黄、
龟甲等↑：β-catenin、LAMP1、V0a1
↓：p-GSK-3β/GSK-3β、p21、IL-8、BACE1D-半乳糖诱导衰老小鼠、APP/PS1小鼠 BV2细胞 促进神经元分化 大补元煎[50]
主要组成：人参片、山药、熟地黄、杜仲、当归、山茱萸、枸杞子、炙甘草↑: β-catenin
↓: GSK-3βAPP/PS1 双转基因小鼠 — 藏药三味豆蔻汤[51]
主要组成：白豆蔻、香旱芹、荜茇↑: Wnt3a、β-catenin、BDNF、
SYP、PSD955×FAD转基因小鼠 —
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