Evaluation of Microcurrent as an Adjunct to Donepezil Therapy in an Alzheimer's Disease Mouse Model: A Pilot Study

Eun Ho Kim¹Yoon-Jin Lee²Yong Suk Moon³Oh Dae Kwon⁴Dong Rak Kwon^5*

• ¹Department of Biochemistry, School of Medicine, Daegu Catholic University, Nam-gu, Daegu, Republic of Korea
• ²Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
• ³Department of Anatomy, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
• ⁴Department of Neurology, School of Medicine, Daegu Catholic University, Nam-gu, Daegu, Republic of Korea
• ⁵Department of rehabilitation medicine, School of Medicine, Daegu Catholic University, Daegu, Republic of Korea

Abstract Background: Alzheimer's disease (AD) is a neurodegenerative disorder due to Aβ plaque accumulation, followed by loss of synapses and decline in cognitive abilities. Donepezil is currently one of the standard pharmacological treatments for Alzheimer's disease. Recently, microcurrent (MC) therapy has emerged as a non-pharmacological adjunct for AD management. Recently, microcurrent therapy emerged as a non-pharmacological alternative to treat AD. Objective: The study investigates the therapeutic outcomes of the MC as an adjuvant to donepezil in mitigating cognitive dysfunction in the transgenic mouse model (5XFAD). Methods: Transgenic 5xFAD mice were assigned to control, donepezil, MC, or MC+donepezil groups. Behavioral performance was assessed using the novel object recognition (NOR) and radial arm maze (RAM) tests. Amyloid burden, glial activation, cytokine expression, apoptotic signaling, and intracellular pathways (PI3K–AKT, AMPK, JAK2/3) were analyzed by immunohistochemistry and Western blotting. Results: Combined treatment with donepezil and microcurrent showed a trend toward improved cognitive performance and reduced pathology compared to donepezil alone, although these differences were not statistically significant. Aβ plaque burden in the cortex and hippocampus was reduced by ~68%, exceeding reductions observed with either treatment alone. Microglial and astroglial activation (Iba1, GFAP, CD68) and pro-inflammatory cytokines (TNF-α, IL-1β) were reduced in both the donepezil and combination groups compared with untreated 5xFAD mice, with no significant difference between 5xD and 5xD + MC. Apoptotic markers (cleaved caspase-3, cleaved PARP) were significantly reduced in both treatment groups compared with untreated controls, but not significantly different between donepezil and combination therapy. At the molecular level, both donepezil and combination therapy activated PI3K–AKT and AMPK signaling and increased inhibitory phosphorylation of GSK-3β compared with untreated 5xFAD mice; no significant difference was observed between the two treatment groups. Conclusion: Donepezil combined with microcurrent therapy showed comparable efficacy to donepezil alone, with numerical trends toward further improvement in cognitive function and pathology, but without statistically significant differences. Both treatments reduced Aβ burden, attenuated glial activation, and modulated survival-related pathways to a similar extent. These findings support a multi-target therapeutic strategy and highlight the translational potential of integrating microcurrent therapy with standard pharmacological treatment for AD.