Academic Blog • Jade Health Acupuncture

Acupuncture, Oxidative Stress, and Alzheimer’s Disease: Nrf2/ARE Pathways in Animal Models

Based on: Huang Y-Y et al., 2021 (PMC8096560)

1. Introduction

Oxidative stress arises when the production of reactive oxygen and nitrogen species exceeds the capacity of the antioxidant defense system. Highly reactive molecules such as hydrogen peroxide, superoxide, and hydroxyl radicals can attack proteins, lipids, and DNA, leading to mitochondrial dysfunction, impaired DNA repair, and progressive cellular injury. These processes are strongly implicated in the pathogenesis of major neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Endogenous antioxidant enzymes — such as heme oxygenase-1 (HO-1), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), glutathione-S-transferase, and NQO1 — help to neutralize excess free radicals. Many of these enzymes are under the control of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which binds to the antioxidant response element (ARE) to switch on a broad cytoprotective program.

The brain is particularly vulnerable to oxidative damage because of its high oxygen consumption and lipid-rich environment. Neurodegenerative diseases are multifactorial, involving genetic and environmental influences, excitotoxicity, protein misfolding, and chronic inflammation, with oxidative stress acting as a unifying driver across these processes.

Acupuncture, rooted in traditional Chinese medicine and practiced for more than 3000 years, now includes several modern forms: manual acupuncture, electroacupuncture (EA), and laser acupuncture. A growing body of evidence suggests that acupuncture can exert antioxidative, anti-inflammatory, and antiapoptotic effects. However, the detailed molecular mechanisms are still being clarified. This review focuses on how acupuncture modulates oxidative stress in AD and PD animal models through the Nrf2/ARE pathway and related signaling cascades.

2. Literature Search Overview

The original article searched PubMed, ClinicalKey, and the Cochrane Library from database inception to June 2020 using combinations of the terms “acupuncture,” “Alzheimer’s disease,” “Parkinson’s disease,” “oxidative damage,” “oxidative stress,” and “Nrf2.” After stepwise screening of titles, abstracts, and full texts, 80 English-language studies were ultimately included for qualitative review.

3. Nrf2/ARE Signaling and Redox Regulation

3.1 Nrf2 structure and Keap1-dependent control

Nrf2 belongs to the leucine zipper family of transcription factors and is a central regulator of redox homeostasis. It contains seven functional domains, termed Nrf2-ECH homology (Neh)1–Neh7:

Neh1 enables Nrf2 dimerization and binding to DNA in the nucleus.
Neh2 mediates binding to kelch-like ECH-associated protein 1 (Keap1), which targets Nrf2 for ubiquitination and proteasomal degradation in the cytosol.
Neh3–Neh5 interact with transcriptional coactivators and contribute to the activation of ARE-driven genes.
Neh6 is a serine-rich region that can be phosphorylated by glycogen synthase kinase (GSK)-3β, promoting nuclear export and degradation of Nrf2.
Neh7 binds retinoic acid receptor alpha and can suppress Nrf2 activity.

Under basal conditions, Nrf2 is largely sequestered in the cytosol by Keap1. Keap1 functions as an adaptor for a cullin-3/RING box protein 1-dependent E3 ubiquitin ligase complex, leading to continuous ubiquitination and degradation of Nrf2. Oxidative or electrophilic stress modifies critical cysteine residues on Keap1, causing conformational changes that release Nrf2. Freed Nrf2 then translocates into the nucleus, binds ARE sequences, and promotes expression of genes that restore redox balance.

3.2 Upstream kinases and Nrf2/ARE control

PKC pathway.

Protein kinase C (PKC) isozymes are serine/threonine kinases involved in apoptosis and autophagy, and dysregulation of PKC activity has been linked to several neurodegenerative conditions. PKC can phosphorylate Nrf2 at Ser40 within the Neh2 domain, facilitating its dissociation from Keap1 and nuclear entry. Stabilization of Nrf2 in the nucleus, however, also depends on Src-family kinase activity, which is itself regulated in a PKCδ-dependent manner under oxidative conditions.

PI3K/Akt/GSK-3β pathway.

The PI3K/Akt pathway plays essential roles in cell growth, survival, differentiation, and metabolism, and provides important neuroprotection against oxidative damage. It is often activated by trophic factors such as nerve growth factor and brain-derived neurotrophic factor (BDNF). BDNF has been shown to promote Nrf2 nuclear translocation in hippocampal neurons in a PI3K-dependent manner, while Nrf2 in turn contributes to maintaining brain BDNF levels, suggesting a bidirectional relationship.

When activated, PI3K/Akt can inhibit GSK-3β. GSK-3β is a negative regulator of Nrf2: it can directly phosphorylate residues within the Neh6 domain to target Nrf2 for degradation, or indirectly promote nuclear Src kinase activity that phosphorylates Nrf2 at specific tyrosine residues, driving nuclear export and further degradation.

p38 MAPK.

p38 mitogen-activated protein kinase (p38 MAPK) is another stress-responsive kinase involved in growth, apoptosis, and inflammation. Depending on context, p38 MAPK can either promote the association of Nrf2 with Keap1 and limit nuclear accumulation, or support ARE-driven transcriptional activity. This dual role may underlie its neurotoxic effects in acute injury versus neuroprotective roles in subacute phases.

NF-κB.

NF-κB is another key transcription factor regulating responses to oxidative stress, typically driving pro-inflammatory gene expression. Oxidative stimuli lead to phosphorylation and degradation of the NF-κB inhibitor IκB, allowing NF-κB to enter the nucleus and induce cytokines such as IL-1, IL-6, TNF-α, and enzymes like iNOS. These molecules further amplify oxidative stress, forming a vicious cycle. Nrf2 can counteract NF-κB signaling by enhancing antioxidant defenses and preventing IκB degradation, while NF-κB can interfere with Nrf2 activity by competing for regulatory regions and limiting ARE-driven transcription.

3.3 Summary of Nrf2/ARE-related pathways

In summary, under homeostatic conditions Nrf2 and NF-κB are held inactive by their inhibitors (Keap1 and IκB) and subjected to continuous degradation. Oxidative stress modifies Keap1 and triggers IκB phosphorylation, releasing Nrf2 and NF-κB. Active Nrf2 enters the nucleus, binds ARE, and induces antioxidant genes. p38 MAPK can either enhance or restrict Nrf2 activity, BDNF can augment Nrf2 accumulation and transactivation via PKC and PI3K signaling, and GSK-3β promotes nuclear export and degradation of Nrf2 unless constrained by PI3K/Akt. Nrf2 also supports mitochondrial biogenesis and quality control, linking redox regulation to cellular energy metabolism.

4. Oxidative Stress and Alzheimer’s Disease

Alzheimer’s disease is the most common cause of dementia worldwide and is projected to affect more than 130 million people by 2050. Clinically, AD is characterized by progressive decline in memory and other cognitive domains, behavioral changes, and language impairment. Pathologically, it features extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau, and loss of cholinergic neurons and synapses.

Aβ1–40/42 peptides are generated from amyloid precursor protein (APP) by sequential cleavage via β- and γ-secretases. In healthy brains, Aβ is cleared by specific degrading enzymes. In AD, disruption of metal ion homeostasis promotes Aβ interaction with zinc, copper, and iron, leading to formation of oligomers and fibrils, both of which are potent inducers of oxidative stress. Oxidative injury in turn worsens mitochondrial dysfunction, triggers caspase activation, and promotes apoptotic pathways.

Severe oxidative stress can open the mitochondrial permeability transition pore, allowing protons, Ca²⁺, and small molecules such as glutathione to cross the inner membrane. Loss of the proton gradient causes mitochondrial depolarization, uncoupling of the respiratory chain, excessive ROS production, depletion of antioxidants, and large Ca²⁺ release. Elevated intracellular Ca²⁺ activates cyclin-dependent kinase 5, which contributes to tau hyperphosphorylation and neurofibrillary tangle formation. Mitochondrial pore opening also releases cytochrome c and other proapoptotic factors, driving caspase-dependent cell death.

5. Effects of Acupuncture on Oxidative Stress in AD Models

Experimental and imaging studies suggest that acupuncture can improve cognitive function by modulating connectivity among key brain regions, including the insula, dorsolateral prefrontal cortex, hippocampus, thalamus, inferior parietal lobule, and anterior cingulate cortex. Proposed mechanisms include increased regional cerebral blood flow, neurotransmitter modulation, enhanced synaptic plasticity, strengthening of endogenous antioxidant defenses, reduced neuronal apoptosis, and, in some models, enhanced neurogenesis.

In AD-related animal work, the acupoints Zusanli (ST36) and Baihui (GV20) are most frequently used to promote hippocampal cell proliferation and neuroprotection.

5.1 Direct modulation of the Nrf2/ARE pathway

Several studies demonstrate that electroacupuncture at Baihui (GV20) can enhance expression of Nrf2, HO-1, and BDNF in the hippocampus, promote neurogenesis, and protect neurons from stress-induced injury. Importantly, these neuroprotective effects are largely lost in Nrf2-knockdown or Nrf2-deficient animals, indicating that the Nrf2/HO-1 axis is essential for the observed benefits.

Combined stimulation of Baihui (GV20) and Zusanli (ST36) has been reported to attenuate cognitive impairment and hippocampal neuronal loss in vascular dementia models, accompanied by increased HO-1 and NQO1 protein levels. Electroacupuncture at Zusanli (ST36) can reduce circulating TNF-α and IL-6, elevate SOD, GSH-Px, and CAT activities, and upregulate HO-1 and Nrf2 expression, suggesting a robust antioxidant response mediated by Nrf2/ARE activation.

Nrf2 has also been implicated in the upregulation of antiapoptotic proteins such as Bcl-2 and Bcl-xL, improving cell survival. Acupuncture at Shenting (GV24) and Benshen (GB13) has been shown to increase Bcl-2 while decreasing Bax, cytochrome c, and caspase-3/9, concurrently lowering ROS and malondialdehyde (MDA) and enhancing SOD activity. These antiapoptotic effects are likely, at least in part, Nrf2 dependent, although further mechanistic work is needed.

5.2 Nrf2/ARE-related signaling cascades

Acupuncture also engages signaling networks that feed into Nrf2/ARE regulation, including PKC, PI3K/Akt/GSK-3β, p38 MAPK, and NF-κB pathways. For example, electroacupuncture has been reported to increase hippocampal PKC expression in depressive models, although direct evidence in AD models remains limited.

In APP/PS1 transgenic mice, electroacupuncture at Baihui (GV20) using alternating 1/20 Hz stimulation for several weeks improved learning and memory and upregulated BDNF expression. Because BDNF can promote Nrf2 nuclear translocation via PI3K signaling, this suggests a link between acupuncture-induced BDNF elevation and enhanced Nrf2/ARE activation. High-frequency electroacupuncture has also been shown to downregulate GSK-3β activity and alleviate cognitive deficits in rodent models.

The downstream target mTOR, a key autophagy regulator in the PI3K/Akt pathway, is also modulated by electroacupuncture. Reduced mTOR activity facilitates autophagy, which can decrease Aβ plaque burden and improve memory. Electroacupuncture at Baihui (GV20) has been reported to lower mTOR levels in APP/PS1 mice, while stimulation at Baihui (GV20), Taixi (KI3), and Zusanli (ST36) can reduce p38 MAPK activation and dampen central nervous system inflammation in AD-like models.

NF-κB signaling is another important target. In multi-infarct dementia models, short daily stimulation at Zusanli (ST36) inhibited nuclear translocation of NF-κB and TP53 in the hippocampus. Electroacupuncture at Baihui (GV20), Yintang (EX-HN3), and Shuigou (GV26) reduced deposition of β-secretase-1, an NF-κB-regulated enzyme involved in Aβ production, in APP/PS1 mice.

5.3 Other antioxidant mechanisms of acupuncture

Beyond Nrf2/ARE, acupuncture can reduce ROS generation by modulating NADPH oxidase (NOX) activity and AMP-activated protein kinase (AMPK) signaling. Electroacupuncture at Baihui (GV20) and Yongquan (KI1) has been shown to inhibit NOX2 expression and decrease hippocampal levels of MDA and 8-hydroxy-2′-deoxyguanosine, a marker of oxidative DNA damage.

The transcriptional coactivator PGC-1α, regulated by AMPK, supports mitochondrial biogenesis and promotes the removal of damaged mitochondria via autophagy-lysosome pathways, thereby limiting ROS production. Electroacupuncture can upregulate PGC-1α expression and improve brain energy metabolism in aging-prone mouse strains.

Members of the heat shock protein (Hsp) family help protect cells under stress by refolding or degrading misfolded proteins and preventing aggregation. Acupuncture at points such as Danzhong (CV17), Zhongwan (CV12), Qihai (CV6), Xuehai (SP10), and Zusanli (ST36) has been associated with reduced oxidative protein damage and increased expression of Hsp84 and Hsp86, which may contribute to delayed brain aging and prevention of neurodegeneration.

6. Summary and Perspective

In AD models, acupuncture appears to ameliorate oxidative stress through at least five complementary mechanisms:

Reducing oxidative stress by enhancing endogenous antioxidant production and limiting ROS generation.
Suppressing apoptosis by modulating signaling pathways downstream of ROS and mitochondrial injury.
Decreasing Aβ production and deposition via effects on enzymes such as β-secretase and autophagy regulation.
Supporting repair or turnover of ROS-damaged proteins, lipids, and DNA.
Alleviating neuroinflammation through interactions with NF-κB and related inflammatory pathways.

Together, these findings suggest that acupuncture can influence a wide redox-regulatory network centered on Nrf2/ARE signaling, while also engaging complementary pathways such as PI3K/Akt, GSK-3β, p38 MAPK, NF-κB, AMPK, and Hsp responses. Although most data come from animal models, the mechanistic insights provide a strong rationale for further clinical research and careful integration of acupuncture into supportive care for patients with cognitive decline.

Main Reference

Huang Y-Y, Lin J-G, Chen Y-H, Hung Y-C, Chen Y-H. Effects of Acupuncture on Oxidative Stress Amelioration via Nrf2/ARE Pathway in Alzheimer’s Disease and Parkinson’s Disease Animal Models. 2021.

Full text: https://pmc.ncbi.nlm.nih.gov/articles/PMC8096560/

學術交流 • Jade Health Acupuncture

針灸、氧化壓力與阿茲海默症： Nrf2/ARE 路徑在動物模型中的研究啟示

文章整理自：Huang Y-Y 等人，2021（PMC8096560）

一、前言

當活性氧（reactive oxygen species, ROS）與活性氮（reactive nitrogen species, RNS）的產生量超過身體抗氧化系統的負荷時，就形成所謂的氧化壓力。高度反應性的 H₂O₂、O₂•⁻、氫氧自由基等分子，會攻擊蛋白質、脂質與 DNA，造成粒線體功能失調、DNA 修復能力下降與細胞損傷，進一步參與阿茲海默症（AD）與巴金森氏症（PD）等神經退行性疾病的發病機轉。

體內重要的抗氧化酵素，包括 heme oxygenase-1（HO-1）、superoxide dismutase（SOD）、glutathione peroxidase（GSH-Px）、 catalase（CAT）、glutathione-S-transferase、NQO1 等，可幫助清除多餘自由基。這些酵素多由核因子紅血球 2 相關因子 2（Nrf2）所調控， Nrf2 可與抗氧化反應元素（ARE）結合，啟動廣泛的細胞保護基因表現。

大腦因高氧氣消耗、脂質含量高而特別容易受到氧化壓力影響。神經退行性疾病的病理機制相當複雜，包含遺傳、環境因子、興奮毒性、蛋白質錯誤摺疊、慢性發炎等，而氧化壓力幾乎貫穿其中所有過程。

針灸源於傳統中醫經絡學說，已在臨床使用超過三千年，包含手針（manual acupuncture）、電針（electroacupuncture, EA）、雷射針灸（laser acupuncture, LA）等形式。近年研究顯示，針灸具有抗氧化、抗發炎與抗細胞凋亡等多重作用，但其分子機轉仍在持續釐清中。本文以 Huang 等人之綜述為主軸，聚焦於針灸如何透過 Nrf2/ARE 及相關訊號路徑，改善 AD、PD 動物模型中的氧化壓力。

二、文獻搜尋概述

原文作者使用 PubMed、ClinicalKey 與 Cochrane Library 等資料庫，以「acupuncture」、「Alzheimer’s disease」、「Parkinson’s disease」、「oxidative damage」、「oxidative stress」、「Nrf2」等關鍵詞單獨或組合檢索，搜尋自資料庫建立至 2020 年 6 月間之英文文獻。經過標題與摘要初篩、全文審閱與排除條件過濾後，最終共納入 80 篇研究進行質性綜整。

三、Nrf2/ARE 訊號與氧化還原調控

3.1 Nrf2 結構與 Keap1 依賴性調控

Nrf2 屬於 leucine zipper 類轉錄因子家族，是維持氧化還原平衡的關鍵轉錄因子。其結構包含七個功能區域，稱為 Nrf2-ECH homology（Neh）1 至 Neh7：

Neh1：使 Nrf2 能在細胞核內與 DNA 結合。
Neh2：促進 Nrf2 與 kelch-like ECH-associated protein 1（Keap1）結合， Keap1 會將 Nrf2 導向泛素化與蛋白酶體降解。
Neh3–Neh5：與轉錄共活化因子及 ARE 相關基因活化有關。
Neh6：為富含絲胺酸的區域，可被 glycogen synthase kinase 3β（GSK-3β）磷酸化，促進 Nrf2 的核外輸出與降解。
Neh7：可與 retinoid acid receptor alpha 結合，抑制 Nrf2 活性。

在穩態條件下，Nrf2 大多被束縛於細胞質內的 Keap1，Keap1 作為 cullin-3/RING box protein 1 依賴性 E3 泛素連接酶複合體的接合蛋白，持續促進 Nrf2 的泛素化與降解。當氧化或親電子壓力升高時，Keap1 上關鍵半胱胺酸殘基發生修飾，使 Nrf2 得以從 Keap1 脫離、轉移入細胞核，與 ARE 結合並啟動抗氧化基因表現，恢復細胞氧化還原平衡。

3.2 上游激酶與 Nrf2/ARE 調控

PKC 路徑

PKC 同功酶屬於絲胺酸/蘇胺酸激酶家族，與細胞凋亡及自噬高度相關，其活性異常與多種神經退行性疾病的進展有關。 PKC 可磷酸化位於 Neh2 區域的 Nrf2 Ser40，促使 Nrf2 自 Keap1 脫離並轉移至細胞核。 Nrf2 在細胞核內的穩定化則與 Src 家族激酶活化有關，而後者受 PKCδ 以及 H₂O₂ 刺激所調控。

PI3K/Akt/GSK-3β 路徑

PI3K/Akt 路徑與細胞生長、生存、分化與代謝密切相關，是對抗氧化損傷的重要神經保護機制之一。此路徑常由神經生長因子（NGF）、腦源性神經滋養因子（BDNF）等營養因子啟動。 BDNF 被證實可透過 PI3K 促進 Nrf2 的核內轉位；相反地，Nrf2 亦有助於維持大腦中 BDNF 水準，顯示兩者間的雙向調控關係。

當 PI3K/Akt 活化時，可抑制 GSK-3β 的活性。 GSK-3β 是 Nrf2 的負向調控者，能直接磷酸化 Neh6 區域，使 Nrf2 透過 SCFβ/TrCP 被降解，也可間接促進核內 Src 激酶活性，進一步磷酸化 Nrf2 特定酪胺酸殘基，促使其核外輸出與降解。

p38 MAPK

p38 MAPK 為絲裂原活化蛋白激酶的一個重要支鏈，參與細胞生長、凋亡與發炎反應。在部分模型中，p38 MAPK 會促進 Nrf2 與 Keap1 的結合、限制 Nrf2 在細胞核的累積；但在其他情況下，p38 MAPK 活化又是 ARE 相關抗氧化效應啟動所必需，呈現急性期偏向神經毒性、次急性期則具神經保護作用的「雙相特性」。

NF-κB 路徑

NF-κB 也是氧化壓力反應中的關鍵轉錄因子，多半驅動促發炎基因表現。氧化壓力會促使其抑制因子 IκB 被磷酸化並降解，使 NF-κB 得以進入細胞核，誘發 IL-1、IL-6、TNF-α、 iNOS 等多種發炎介質表現，進一步加劇氧化壓力，形成惡性循環。 Nrf2 則可透過提升抗氧化能力、抑制 IκB 降解來對抗 NF-κB 活化；同時 NF-κB 也可競爭性阻礙 ARE 區域，干擾 Nrf2 所驅動的轉錄活性。

3.3 Nrf2/ARE 相關路徑摘要

簡言之，在穩態條件下，Nrf2 與 NF-κB 分別被 Keap1 與 IκB 抑制並持續降解；一旦氧化壓力升高，Keap1 結構被修飾、IκB 被磷酸化，Nrf2 與 NF-κB 便從抑制因子中釋放。活化的 Nrf2 進入細胞核，與 ARE 結合並啟動抗氧化基因；p38 MAPK、BDNF/PKC、PI3K/Akt/GSK-3β、 NF-κB 等路徑共同調控 Nrf2 的核內外動態與轉錄活性。此外，Nrf2 亦參與粒線體新生與品質控制，將氧化還原調節與能量代謝緊密連結。

四、氧化壓力與阿茲海默症（AD）

阿茲海默症是全球最常見的失智症成因，預估至 2050 年將影響超過 1.31 億人口。臨床上以記憶力與多面向認知功能逐漸惡化為主，伴隨行為改變與語言功能退化。病理上則以 β 類澱粉蛋白（Aβ）斑塊、過度磷酸化 tau 形成的神經纖維糾結、以及膽鹼能神經元與突觸流失為特徵。

Aβ1–40/42 為類澱粉前體蛋白（APP）經 β 與 γ 分泌酶連續切割而來，在正常大腦中可藉由特定降解酵素清除。在 AD 患者，由於金屬離子恆定性失衡，Aβ 容易與鋅、銅、鐵等金屬結合，形成寡聚體與纖維，而這些結構本身即可強烈誘發氧化壓力，進一步惡化粒線體功能、啟動半胱天冬酶，走向細胞凋亡途徑。

嚴重氧化壓力可導致粒線體通透性轉變孔（mPTP）開啟，使質子、Ca²⁺ 及小分子（如 GSH）穿越內膜，造成粒線體去極化、呼吸鏈解偶合、ROS 暴增、抗氧化物耗竭與 Ca²⁺ 大量釋放。細胞內 Ca²⁺ 增加會活化 CDK5，促使 tau 過度磷酸化，形成神經纖維糾結； mPTP 開啟也會釋放 cytochrome c 與多種促凋亡因子，最後導致凋亡性細胞死亡。

五、針灸在 AD 模型中改善氧化壓力的作用

影像與動物實驗研究顯示，針灸可藉由調整多個認知相關腦區之間的連結性，來改善認知功能，包括島葉、背外側前額葉皮質、海馬、丘腦、下頂葉小葉與前扣帶迴等。其可能機制包括：增加局部腦血流、調控神經傳導物質、改善突觸可塑性、增強內源性抗氧化系統、降低神經元凋亡，以及在部分模型中促進神經新生。

在 AD 相關動物研究中，最常被用來促進海馬細胞增殖與神經保護的穴位為 足三里（ST36）與百會（GV20）。

5.1 直接活化 Nrf2/ARE 路徑

多項研究顯示，百會（GV20）電針可提升海馬中 Nrf2、HO-1 與 BDNF 表現，促進神經新生並保護神經元免於壓力相關損傷。值得注意的是，在 Nrf2-knockdown 或 Nrf2 缺失動物中，這些神經保護效果大幅減弱或消失，顯示 Nrf2/HO-1 軸線是電針神經保護作用的關鍵。

另一研究指出，百會（GV20）合併足三里（ST36）針刺可改善血管性失智模型中的認知功能與海馬神經元減少，並顯著提升 HO-1 與 NQO1 蛋白表現。足三里（ST36）電針亦被證實可降低血漿 TNF-α 與 IL-6，增加 SOD、GSH-Px、CAT 活性，並上調 HO-1 與 Nrf2 表現，顯示其透過活化 Nrf2/ARE 路徑，對抗氧化壓力誘發的組織損傷。

此外，Nrf2 還與抗凋亡蛋白 Bcl-2、Bcl-xL 的上調有關，有助於提升細胞存活。研究顯示，神庭（GV24）與本神（GB13）針刺可上調 Bcl-2、下調 Bax、cytochrome c 與 caspase-3/9，同時降低 ROS 與 MDA、提升 SOD，其抗凋亡效果被推測與 Nrf2 調控相關，但仍需更多研究確認。

5.2 Nrf2/ARE 相關訊號途徑

除了直接活化 Nrf2/ARE 外，針灸亦可透過 PKC、PI3K/Akt/GSK-3β、p38 MAPK、NF-κB 等訊號路徑間接調控 Nrf2。例如電針曾被報告可提升憂鬱模型中海馬的 PKC 表現，但在 AD 模型中的相關研究仍較少。

在 APP/PS1 易感性小鼠中，百會（GV20）電針以 1/20 Hz 交替波、每日 30 分鐘、連續數週，可改善學習與記憶，並上調 BDNF 表現。鑑於 BDNF 能透過 PI3K 促進 Nrf2 核內轉位，這暗示針灸提升 BDNF 的同時，也可能強化 Nrf2/ARE 活性。另有研究指出，高頻電針可下調 GSK-3β 活性、改善大鼠認知缺損。

PI3K/Akt 下游的 mTOR 是自噬的重要調控者。mTOR 活性下降可促進自噬，減少 Aβ 斑塊沉積並改善記憶。在 APP/PS1 小鼠中，百會（GV20）電針可降低 mTOR 水準；於 AD 大鼠模型中，百會（GV20）、太溪（KI3）、足三里（ST36）以 1 mA、2 Hz、每日 15 分鐘、共 12 次的電針療程，則能降低 p38 MAPK 活性、抑制中樞神經系統發炎反應。

NF-κB 訊號亦是針灸的重要標的。多發性腦梗塞模型中，足三里（ST36）每日短暫針刺可抑制海馬 NF-κB 與 TP53 的核內轉位；百會（GV20）、印堂（EX-HN3）、水溝（GV26）電針則可降低 APP/PS1 小鼠中 β-secretase-1 的沉積，而該酵素正是受 NF-κB 調控、參與 Aβ 生成的重要因子。

5.3 其他抗氧化機制

除 Nrf2/ARE 外，針灸亦可透過調控 NADPH oxidase（NOX）與 AMP-activated protein kinase（AMPK）等路徑，直接降低 ROS 產生。研究顯示，百會（GV20）合併湧泉（KI1）電針可抑制 NOX2 表現，減少海馬中 MDA 及 8-hydroxy-2′-deoxyguanosine（8-OHdG，DNA 損傷標記）的累積。

AMPK 調控的 PGC-1α 參與粒線體新生以及透過自噬-溶酶體系統清除受損粒線體，因而可減少 ROS 產生。電針被證實可上調 PGC-1α 表現，並改善老化易感小鼠大腦的能量代謝。

另外，熱休克蛋白（heat shock proteins, Hsp）家族可在壓力下幫助折疊或降解錯誤摺疊蛋白，防止異常蛋白聚集，對細胞具有保護作用。有研究發現，膻中（CV17）、中脘（CV12）、氣海（CV6）、雙側血海（SP10）、足三里（ST36）針刺，可減少氧化蛋白損傷並提升 Hsp84 與 Hsp86 表現，可能延緩腦老化並預防神經退行性變化。

六、總結與展望

綜合目前 AD 動物模型的證據，針灸似乎透過以下五個方向改善氧化壓力：

降低氧化壓力：提升內源性抗氧化產生、抑制 ROS 生成。
抑制凋亡：調控 ROS 下游訊號與粒線體損傷途徑，減少細胞凋亡。
減少 Aβ 產生與沉積：透過 β-secretase、mTOR、自噬等路徑降低 Aβ 負荷。
修復受損生物分子：協助清除或修復被 ROS 破壞的蛋白質、脂質與 DNA。
緩解神經發炎：透過影響 NF-κB 等發炎訊號，減少發炎與二次性氧化傷害。

整體而言，針灸對 Nrf2/ARE 為核心的紅氧調控網路具有多重影響，同時牽涉 PI3K/Akt、GSK-3β、 p38 MAPK、NF-κB、AMPK、Hsp 等路徑。雖然目前證據多來自動物研究，但這些機轉性發現提供了強而有力的生物學基礎，支持未來在臨床上將針灸謹慎地整合進認知退化患者的支持性照護中。

主要參考文獻

線上全文： https://pmc.ncbi.nlm.nih.gov/articles/PMC8096560/