Electroacupuncture improves learning-memory and hippocampal myelin in AD mice by modulating Rac1/PAK1/LIMK1/cofilin pathway

Alzheimer's disease (AD) is characterized by progressive cognitive decline, with neurodegeneration and synaptic dysfunction playing critical roles. Myelin sheath integrity in the hippocampus is crucial for efficient neuronal communication and memory formation, and its degradation is implicated in AD pathology. Current treatments offer symptomatic relief but lack disease-modifying capabilities. The Rac1/PAK1/LIMK1/cofilin signaling pathway is a key regulator of actin cytoskeleton dynamics, essential for synaptic plasticity, neuronal morphology, and myelin maintenance, representing a promising target for AD interventions.

Researchers investigated the effects of electroacupuncture (EA) in male senescence-accelerated mouse prone 8 (SAMP8) mice, an AD model. Nine SAMP8 mice were assigned to a model group and nine to an EA group, with nine age-matched SAMR1 mice serving as controls. The EA group received electroacupuncture at "Dazhui" (GV14) and "Shenshu" (BL23) with needling at "Baihui" (GV20) for 20 min, once per day, for a total of 24 days (with 2-day rests after every 8 days). Learning-memory was assessed via the Morris water maze test. Hippocampal myelin was observed using Luxol fast blue (LFB) staining, and cytoskeleton integrity with phalloidin staining. mRNA and protein expression of Rac1, PAK1, LIMK1, cofilin, and myelin basic protein (MBP) were quantified by real-time fluorescence quantitative PCR and Western blot, respectively.

Compared to control mice, the AD model group exhibited an obvious increase in Morris water maze escape latency (P<0.01), alongside significant decreases in platform-crossing frequency and time spent in the target quadrant (P<0.01). This was coupled with reduced hippocampal cytoskeleton fluorescence intensity, lower mRNA levels of Rac1, PAK1, LIMK1, and cofilin, and decreased protein levels of MBP and Rac1 (P<0.01). Furthermore, the ratios of p-PAK1/PAK1, p-LIMK1/LIMK1, and p-cofilin/cofilin were significantly reduced in the model group (P<0.01), indicating dysregulation of cytoskeletal dynamics. Following electroacupuncture intervention:

EA treatment significantly reversed the increased escape latency and restored the decreased platform-crossing frequency and target quadrant time to near control levels (P<0.01). EA also significantly increased hippocampal MBP protein expression and cytoskeleton fluorescence intensity (P<0.01). Moreover, EA normalized the mRNA and protein expression of Rac1, PAK1, LIMK1, and cofilin, and restored the p-PAK1/PAK1, p-LIMK1/LIMK1, and p-cofilin/cofilin ratios in the hippocampus (P<0.01), suggesting a restoration of cytoskeletal regulatory pathways.