Electroacupuncture Attenuates High‐Fat Diet‐Exacerbated Alzheimer's Pathology by Enhancing TFEB/TFE3‐Mediated Autophagic Clearance of Tau and NLRP3 Inflammasome in 3xTg Mice

ABSTRACT Background Alzheimer's disease (AD) pathology is increasingly linked to metabolic disturbances induced by high‐fat diets (HFD), with both autophagy‐lysosomal pathway (ALP) dysfunction and activation of the NLRP3 inflammasome emerging as key pathological mechanisms. This study introduces a novel approach using electroacupuncture (EA) to mitigate HFD‐accelerated AD pathology, focusing on the regulatory role of transcription factors TFEB and TFE3 in ALP and their potential modulation by EA. Methods 3xTg‐AD mice were fed either an HFD or a standard diet for 16 weeks, followed by EA treatment at the ST36 acupoint. AAV‐mediated hippocampal knockdown of TFEB and TFE3 was performed using shRNA constructs. Cognitive performance was evaluated with the Morris water maze (MWM) and Y‐maze tests. Molecular analyses, including immunoblotting and immunohistochemistry, were conducted to examine the impact of EA on NLRP3 inflammasome activation, ALP dynamics, and the involvement of TFEB and TFE3 in modulating these pathways within the brain. Results HFD feeding significantly exacerbated Tau pathology and NLRP3 inflammasome activation in 3xTg‐AD mice, leading to pronounced cognitive deficits. Notably, EA‐ST36 intervention reversed these pathological effects, enhancing memory function and reducing both Tau aggregation and NLRP3 inflammasome activation. Mechanistic insights revealed that EA‐ST36 activated TFEB and TFE3 by modulating the MTOR/ULK1 signaling pathway, thereby enhancing autophagic clearance of NLRP3 inflammasome components and Tau aggregates. Conclusion This study proposes EA‐ST36 as a promising therapeutic strategy for counteracting HFD‐induced AD pathology by activating TFEB/TFE3‐driven autophagic pathways, thereby enhancing the clearance of toxic protein aggregates and inflammasome components. These findings advance our understanding of EA's molecular mechanisms in AD therapy, offering a novel, nonpharmacological approach for mitigating diet‐induced exacerbation of neurodegenerative processes.