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Published on: December 8, 2023
Electroacupuncture ameliorates tau-driven cognitive decline by modulating NF-κB/NLRP3 inflammasome signaling in P301S
Ruixue Zheng1, Xueyun Liu1, Zhenge Liao1
1Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.
Abstract:
Alzheimer's disease (AD) progression is driven by a vicious cycle wherein pathological Tau hyperphosphorylation promotes microglial activation and NF-κB/NLRP3 inflammasome signaling, leading to excessive secretion of proinflammatory cytokines that reciprocally exacerbate Tau pathology. While pharmacological NLRP3 inhibitors hold therapeutic potential for AD, critical barriers-including poor blood-brain barrier penetration, suboptimal target selectivity, and safety concerns-persist. This study investigated whether electroacupuncture (EA), a non-pharmacological neuromodulatory approach, could disrupt this Tau-inflammasome cycle. Using P301S Tau transgenic mice, two EA regimens were tested at the GV20 (Baihui) acupoint: 6-month-old mice receiving a 1-month EA intervention, and 6-month-old mice undergoing a prolonged 3-month EA intervention. Cognitive function was evaluated via Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests, while corticospinal function was assessed using tail-suspension limb-clasping scoring. Hippocampal Tau pathology and inflammatory signaling were analyzed by Western blot and immunohistochemistry, targeting total Tau, phosphorylated Tau, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and microglial morphology. Short-term (1-month) EA treatment significantly improved spatial working memory and recognition memory. Mechanistically, EA reduced p-Tau levels, suppressed NF-κB activation (decreased p-P65/P65 ratio), downregulated NLRP3 inflammasome components (NLRP3, cleaved caspase-1) and proinflammatory cytokines (IL-1β, IL-18 and TNF-α), and mitigated microglial hyperactivation. Importantly, long-term (3-month) EA treatment persistently suppressed p-Tau accumulation and neuroinflammation, thereby consolidating cognitive benefits even in P301S mice with severe corticospinal dysfunction. These findings establish EA as a multi-targeted immunomodulatory strategy that attenuates Tau-driven neuroinflammation through the TNF-α/NF-κB/NLRP3 signaling axis, highlighting its potential as a safe, non-pharmacological adjunct or alternative therapy for AD and related tauopathies.
Insights
Electroacupuncture (EA) therapy effectively reduces Tau pathology and neuroinflammation in Alzheimer's disease models. This non-pharmacological approach improves cognitive function by targeting the TNF-α/NF-κB/NLRP3 signaling pathway.
Area of Science:
- Neuroscience
- Immunology
- Integrative and Complementary Medicine
Background:
- Alzheimer's disease (AD) progression involves a detrimental cycle of Tau hyperphosphorylation, microglial activation, and neuroinflammation via the NF-κB/NLRP3 inflammasome pathway.
- Existing pharmacological NLRP3 inhibitors face challenges like poor blood-brain barrier penetration and safety concerns, limiting their therapeutic application in AD.
Purpose of the Study:
- To investigate the efficacy of electroacupuncture (EA), a non-pharmacological neuromodulatory technique, in disrupting the Tau-driven neuroinflammatory cycle in a mouse model of AD.
- To elucidate the underlying molecular mechanisms by which EA modulates Tau pathology and neuroinflammation.
Main Methods:
- P301S Tau transgenic mice received either 1-month or 3-month EA interventions at the GV20 acupoint.
- Cognitive functions were assessed using behavioral tests (Y-maze, NOR, MWM).
- Hippocampal tissues were analyzed for Tau pathology, NF-κB/NLRP3 inflammasome activation, pro-inflammatory cytokines (IL-1β, IL-18, TNF-α), and microglial morphology using Western blot and immunohistochemistry.
Main Results:
- Short-term EA treatment significantly improved spatial working and recognition memory, reduced phosphorylated Tau (p-Tau) levels, and suppressed NF-κB activation and NLRP3 inflammasome components.
- EA treatment mitigated microglial hyperactivation and decreased levels of pro-inflammatory cytokines IL-1β, IL-18, and TNF-α.
- Long-term EA treatment sustained the suppression of p-Tau and neuroinflammation, leading to persistent cognitive benefits, even in mice with severe corticospinal dysfunction.
Conclusions:
- Electroacupuncture serves as a multi-targeted immunomodulatory strategy that effectively attenuates Tau-driven neuroinflammation.
- EA disrupts the Tau-inflammasome cycle by targeting the TNF-α/NF-κB/NLRP3 signaling axis.
- EA demonstrates potential as a safe, non-pharmacological adjunctive or alternative therapy for Alzheimer's disease and related tauopathies.
