Acupuncture and Oxidative Stress in Alzheimer’s Disease

1. How Acupuncture Engages the “Cognitive Network” in AD Models

In experimental Alzheimer’s disease (AD) models, acupuncture appears to influence the brain not just at a single point, but at the level of network organization. Functional imaging and animal studies suggest that acupuncture can reshape connectivity among multiple cognition-related regions, including the insula, dorsolateral prefrontal cortex, hippocampus, thalamus, inferior parietal lobule, and anterior cingulate cortex. These changes in network coordination are thought to underlie improvements in memory, attention, and learning observed in some models.

Mechanistically, several processes have been proposed:

• Enhancement of regional cerebral blood flow and oxygen delivery
• Fine-tuning of excitatory and inhibitory neurotransmission
• Improvement of synaptic plasticity and network adaptability
• Activation of endogenous antioxidant defense systems
• Reduction of neuronal apoptosis
• Promotion of neurogenesis in selected models

When the goal is to protect the hippocampus and support cell proliferation, two acupoints emerge again and again in the literature: Zusanli (ST36) and Baihui (GV20). They are often used as a core pair in AD-related animal studies.

2. Direct Activation of the Nrf2/ARE Antioxidant Axis

A consistent theme across multiple studies is that electroacupuncture at Baihui (GV20) can directly boost the Nrf2/ARE antioxidant axis within the hippocampus. Stimulation at this point has been shown to:

• Increase Nrf2 protein levels and nuclear translocation
• Upregulate HO-1 and other antioxidant enzymes
• Enhance brain-derived neurotrophic factor (BDNF) expression
• Support neurogenesis and neuronal survival under stress

Importantly, when Nrf2 is genetically knocked down or deleted, these protective effects are largely abolished. This strongly suggests that the Nrf2/HO-1 axis is not just “involved,” but is central to the neuroprotective actions of electroacupuncture in these models.

When Baihui (GV20) is combined with Zusanli (ST36), the effects extend beyond single markers. In vascular dementia and AD-related models, this combination can:

• Improve learning and memory performance
• Reduce hippocampal neuronal loss
• Increase HO-1 and NQO1 expression
• Decrease systemic inflammation (lower TNF-α, IL-6) while boosting SOD, GSH-Px, and CAT activity

Together, these findings depict GV20+ST36 not simply as “symptom points,” but as a pair that actively re-engages the Nrf2/ARE antioxidant machinery and counters oxidative damage at the tissue level.

Beyond antioxidant actions, Nrf2 is also linked to the decision of whether a stressed neuron undergoes apoptosis. Experimental work suggests that Nrf2 can upregulate antiapoptotic proteins such as Bcl-2 and Bcl-xL. Acupuncture at Shenting (GV24) and Benshen (GB13) has been shown to increase Bcl-2 while lowering Bax, cytochrome c, and caspase-3/9, accompanied by decreased ROS and malondialdehyde (MDA) and increased SOD activity. These patterns point toward Nrf2-mediated modulation of intrinsic apoptotic pathways, though the exact links remain to be fully mapped.

3. Indirect Modulation through Nrf2-Related Signaling Networks

Nrf2 does not operate in isolation. It is embedded in a broader web of signaling pathways, many of which are responsive to acupuncture. Key players include PKC, PI3K/Akt/GSK-3β, p38 MAPK, and NF-κB.

3.1 PKC and Nrf2

Protein kinase C (PKC) can phosphorylate Nrf2 and promote its release from Keap1, setting the stage for nuclear entry. Electroacupuncture has been reported to increase hippocampal PKC expression in certain models of depression. While direct data in AD models are still limited, these findings suggest that at least part of acupuncture’s influence on Nrf2 may be mediated via PKC-dependent priming.

3.2 PI3K/Akt, GSK-3β, and BDNF

The PI3K/Akt pathway acts as a “pro-survival switch” in neurons. In APP/PS1 transgenic mice, repeated electroacupuncture at Baihui (GV20) with alternating 1/20 Hz stimulation for 30 minutes a day over several weeks improves spatial learning and memory and significantly elevates BDNF levels. Because BDNF can drive Nrf2 nuclear translocation via PI3K, this suggests that acupuncture may enhance Nrf2/ARE signaling indirectly by raising BDNF and engaging PI3K/Akt.

GSK-3β is a major negative regulator of Nrf2. High-frequency electroacupuncture has been shown to suppress GSK-3β activity and improve cognitive deficits in rodent models, effectively “releasing the brake” on Nrf2 and allowing antioxidant and cytoprotective programs to proceed more fully.

3.3 mTOR, Autophagy, and Aβ Burden

Downstream of PI3K/Akt, the mTOR complex is a central regulator of autophagy. Lowering mTOR activity can enhance autophagic clearance of misfolded proteins and reduce Aβ plaque burden. In APP/PS1 mice, electroacupuncture at Baihui (GV20) has been reported to decrease mTOR levels. In an AD rat model, a protocol combining Baihui (GV20), Taixi (KI3), and Zusanli (ST36) at 1 mA, 2 Hz for 15 minutes daily over 12 sessions reduced p38 MAPK activation and dampened central inflammatory responses. These observations place acupuncture at the intersection of redox modulation, protein clearance, and neuroinflammation.

3.4 NF-κB: Linking Inflammation and Aβ Production

NF-κB functions as a major amplifier of inflammatory and oxidative signals. In multi-infarct dementia models, brief daily acupuncture at Zusanli (ST36) inhibits nuclear translocation of NF-κB and TP53 in the hippocampus, suggesting reduced activation of stress and cell-death programs. In APP/PS1 mice, electroacupuncture at Baihui (GV20), Yintang (EX-HN3), and Shuigou (GV26) reduces accumulation of β-secretase-1, an NF-κB-regulated enzyme central to Aβ generation. These findings indicate that acupuncture can act both upstream (by modulating NF-κB) and downstream (by affecting β-secretase-1) in pathways that drive Aβ pathology.

4. Beyond Nrf2: Additional Antioxidant and Cytoprotective Mechanisms

4.1 NOX and the Sources of ROS

NADPH oxidases (NOXs) are major enzymatic sources of ROS. In animal models, electroacupuncture at Baihui (GV20) plus Yongquan (KI1) has been shown to suppress NOX2 expression and decrease hippocampal levels of MDA and 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. This suggests that acupuncture can act not only by enhancing antioxidant defenses, but also by turning down ROS production at its source.

4.2 AMPK–PGC-1α and Mitochondrial Quality Control

AMPK serves as an energy sensor in neurons, and its downstream effector PGC-1α coordinates mitochondrial biogenesis and the removal of damaged mitochondria through autophagy–lysosome pathways. By improving mitochondrial quality, PGC-1α helps limit ROS production. Electroacupuncture has been reported to upregulate PGC-1α and improve brain energy metabolism in aging-prone mice, linking acupuncture to healthier, more resilient “cellular power plants.”

4.3 Heat Shock Proteins and Protein Homeostasis

Heat shock proteins (Hsps) form another protective layer by refolding or targeting misfolded proteins for degradation, thereby preventing toxic aggregation. Acupuncture at Danzhong (CV17), Zhongwan (CV12), Qihai (CV6), bilateral Xuehai (SP10), and Zusanli (ST36) has been associated with reduced oxidative protein damage and increased expression of Hsp84 and Hsp86. These changes may contribute to delayed brain aging and reduced vulnerability to neurodegenerative processes.

5. Clinical Perspective

Taken together, the experimental data suggest that acupuncture can modulate oxidative stress in AD models through multiple, converging mechanisms:

• Strengthening endogenous antioxidant defenses (Nrf2/ARE axis)
• Reducing ROS production at enzymatic sources such as NOX2
• Protecting mitochondria and improving energy metabolism
• Limiting apoptosis and inflammatory signaling (NF-κB, TP53)
• Influencing Aβ generation and clearance (β-secretase, autophagy)

Although these findings come largely from animal studies, they provide a mechanistic framework for understanding why some patients with cognitive decline may report better clarity, stability, or resilience when acupuncture is used as part of a broader, integrative care plan.

一、針灸如何在 AD 模型中調整「認知網路」

近年的影像與動物實驗顯示，針灸對大腦的影響並非只限於「局部止痛」， 而是會在更高層級上重新調整多個與認知功能相關的腦區網路。 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區域， 在針灸刺激後，其連結方式與同步活動都可能改變， 被認為與記憶、專注與學習能力的改善有關。

從機制角度來看，目前研究提出的可能路徑包括：

• 提升局部腦血流與氧氣供應
• 調整興奮性與抑制性神經傳導物質的平衡
• 增強突觸可塑性與腦網路適應能力
• 啟動內源性抗氧化防禦系統
• 減少神經元凋亡
• 在部分模型中促進神經新生（neurogenesis）

在阿茲海默症相關動物研究中，若研究目標是保護海馬、促進細胞增生， 足三里（ST36）與百會（GV20）幾乎是最常見的「核心穴位組合」。

二、直接啟動 Nrf2/ARE 抗氧化軸

多篇研究指出，對百會（GV20）施以電針刺激，可以顯著提升海馬區域中 Nrf2、HO-1 與 BDNF 的表現，一方面強化抗氧化能力，一方面促進新生神經元形成， 讓神經細胞在壓力環境下比較不容易受損。

一個非常關鍵的觀察是：當研究者使用 Nrf2-knockdown 或 Nrf2 基因缺失動物時， 同樣的電針刺激就幾乎不再能提供神經保護效果。 這個結果強烈暗示：Nrf2/HO-1 軸線不是「附帶參與」，而是電針產生神經保護與抗氧化作用的核心通路。

當百會（GV20）與足三里（ST36）合併使用時，效果更從單一指標擴展到整體功能層面。 在血管性失智與 AD 相關模型中，這組穴位可以：

• 改善學習與記憶表現
• 減少海馬神經元流失
• 提升 HO-1 與 NQO1 蛋白表現
• 降低 TNF-α、IL-6 等發炎因子，同時提高 SOD、GSH-Px、CAT 等抗氧化酵素活性

整體來看，GV20＋ST36 並非只是「症狀對應穴位」，而是實際參與啟動 Nrf2/ARE 抗氧化機制， 幫助組織抵消氧化壓力造成的傷害。

此外，Nrf2 也牽涉到細胞是否進入凋亡路徑的關鍵決策。 研究發現，Nrf2 可上調 Bcl-2、Bcl-xL 等抗凋亡蛋白，提升細胞存活率。 在神庭（GV24）與本神（GB13）針刺的實驗中，可見： Bcl-2 上升、Bax、cytochrome c 與 caspase-3/9 下調，同時 ROS 與 MDA 降低、SOD 活性提升。 這些變化點向同一方向：針灸透過 Nrf2 相關路徑，調整細胞內部的「凋亡開關」， 讓神經元有更多機會在高壓環境下存活。不過，細部機轉仍需要更多研究釐清。

三、透過 Nrf2 相關訊號網路的間接調控

在細胞內部，Nrf2 被置放在一張龐大的訊號網路中心，其中多條路徑都會回頭影響 Nrf2/ARE 活性。 針灸在實驗中被觀察到會同時動到多條訊號，包括 PKC、PI3K/Akt/GSK-3β、p38 MAPK、NF-κB 等。

3.1 PKC 與 Nrf2

PKC 可磷酸化 Nrf2，使其較易脫離 Keap1、進入細胞核。 部分動物研究顯示，電針能提升海馬 PKC 活性。 雖然在 AD 模型中，直接連結「針灸–PKC–Nrf2」的研究仍有限， 但已有跡象顯示 PKC 可能是針灸協助「預備」Nrf2 活化的一個環節。

3.2 PI3K/Akt、GSK-3β、BDNF 與 Nrf2

PI3K/Akt 路徑在神經細胞裡扮演「生存開關」的角色。 在 APP/PS1 轉基因小鼠中，對百會（GV20）施以 1/20 Hz 交替波電針，每日 30 分鐘、持續數週， 可以明顯改善空間學習與記憶，並提升 BDNF 水準。 由於 BDNF 已被證實可透過 PI3K 促進 Nrf2 轉位到細胞核， 這表示針灸提高 BDNF 的同時，很可能也在「從上游推動」Nrf2/ARE 抗氧化軸。

另一方面，GSK-3β 是 Nrf2 的重要「煞車」。 高頻電針在動物研究中被發現可抑制 GSK-3β 活性，並改善認知缺損， 等於是幫 Nrf2 鬆開束縛，讓其更完整地啟動抗氧化與細胞保護程式。

3.3 mTOR、自噬與 Aβ 負荷

在 PI3K/Akt 的下游，mTOR 是細胞自噬的關鍵調控者。 當 mTOR 活性下降，自噬機制被啟動，有助於清除錯誤摺疊蛋白、降低 Aβ 斑塊負荷、改善記憶表現。 APP/PS1 小鼠研究顯示，百會（GV20）電針可降低 mTOR 水準。

在另一個 AD 大鼠模型中，百會（GV20）、太溪（KI3）、足三里（ST36）電針（1 mA、2 Hz、每日 15 分鐘，共 12 次）， 則被發現可以降低 p38 MAPK 活性、抑制中樞神經系統的發炎反應。 這些結果讓我們看到：針灸同時在「抗氧化」、「蛋白質清除」與「抗發炎」幾個層面交會。

3.4 NF-κB：發炎與 Aβ 生成的交會點

NF-κB 是發炎與氧化壓力的放大器。 在多發性腦梗塞模型中，足三里（ST36）每日短暫針刺，被發現可抑制海馬 NF-κB 與 TP53 的核內轉位， 代表細胞壓力與死亡訊號被部分關掉。

在 APP/PS1 小鼠中，百會（GV20）、印堂（EX-HN3）、水溝（GV26）電針可降低 β-secretase-1 的沉積， 而 β-secretase-1 正是受 NF-κB 調控、參與 Aβ 生成的重要酵素。 換句話說，針灸不僅在處理「結果」（Aβ 沉積），也同時在上游調整「造成 Aβ 過度產生的訊號」。

四、超越 Nrf2：其他與氧化壓力相關的保護機制

4.1 NOX 與 ROS 來源

NADPH oxidase（NOX）是 ROS 的主要酵素來源之一。 動物實驗顯示，百會（GV20）合併湧泉（KI1）電針可以抑制 NOX2 表現， 並降低海馬中 MDA 與 8-OHdG（DNA 損傷標記）的累積。 這代表針灸不僅在「下游」清除氧化傷害，也直接從「源頭」減少 ROS 的產生。

4.2 AMPK–PGC-1α 與粒線體品質控制

AMPK 是細胞能量感測器，其下游 PGC-1α 則負責調控粒線體新生， 並透過自噬–溶酶體系統清除受損粒線體。 當粒線體品質提升時，整體 ROS 產量自然會下降。 實驗發現，電針可上調 PGC-1α 表現，並改善老化易感小鼠大腦的能量代謝， 讓神經細胞的「發電廠」更穩定、不那麼容易外漏自由基。

4.3 熱休克蛋白（Hsp）與蛋白品質管理

熱休克蛋白（heat shock proteins, Hsp）家族在壓力環境下， 可協助新生蛋白正確折疊，或將錯誤摺疊蛋白重新折疊、標記降解， 避免有毒蛋白聚集。

有研究發現，針刺膻中（CV17）、中脘（CV12）、氣海（CV6）、雙側血海（SP10）、足三里（ST36）， 可減少氧化蛋白損傷並提升 Hsp84 與 Hsp86 表現， 可能有助於延緩腦老化、降低神經退行性變化的風險。

五、臨床觀點小結

綜合目前阿茲海默症動物模型的證據，針灸似乎透過多個互相連結的層面來調節氧化壓力：

• 強化 Nrf2/ARE 為核心的內源性抗氧化系統
• 從 NOX2 等酵素來源減少 ROS 生成
• 透過 AMPK–PGC-1α 改善粒線體品質與能量代謝
• 調降 NF-κB、TP53 等發炎與壓力訊號，減少凋亡
• 藉由 mTOR、自噬與 β-secretase 等路徑影響 Aβ 的生成與清除

雖然這些結果主要來自動物實驗，但它們提供了相當具體的生物學框架， 帶我們理解為何在臨床實務中，部分認知退化患者在接受規劃良好的針灸治療後， 會主觀感受到「頭腦比較清楚、比較穩定」。 對臨床工作者而言，較合理的做法，是將針灸視為一種有機轉基礎的整合療法選項， 與現代醫學治療、復健與生活調整並行，而非替代。