tDCS improves early Alzheimer’s disease by synaptic vesicle fusion and release

Yue-Yang Zhuang; Jia-Min Yan; Tie-Cheng Wu; Wen-Shan Xu; Bao Wu; Xi Xie; Wen-Ju Wang; Hua-Wei Lin; Jia-Wei Jian; Jun-Zi Wang; Tao Jiang; Li-Ming Chen; Yu-Xi Qiu; Zhong-Yi Hu; Yi-Hui Zhou; Ting Yang; Min-Guang Yang; Jing-Fang Zhu; Jing Tao; Li-Dian Chen; Wei-Guang Li; Kai Yan; Wei-Lin Liu

doi:10.1016/j.mmr.2026.100003

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tDCS improves early Alzheimer’s disease by synaptic vesicle fusion and release

RESEARCH | Updated：2026-05-11

- tDCS improves early Alzheimer’s disease by synaptic vesicle fusion and release
- Military Medical Research (2026)
- Affiliations：
  
  The Institute of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
  National-Local Joint Engineering Research Center of Rehabilitation Medicine Technology, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
  State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
  The State Key Laboratory of Brain and Cognitive Sciences, the University of Hong Kong, Hong Kong SAR 999077, China
  Children Hospital of Fudan University, Shanghai 201102, China
- Author bio：
  
  *Wei-Guang Li, wgli@icmm.ac.cn;
  Kai Yan, fhyankai@gmail.com;
  Wei-Lin Liu, liuweilin12@fjtcm.edu.cn
- Funds：
- DOI：10.1016/j.mmr.2026.100003
  CLC：
- Received：26 August 2025，
  
  Revised：2026-03-05，
  
  Published：2026-03
- Accepted：
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Zhuang YY, Yan JM, Wu TC, Xu WS, Wu B, Xie X, et al. tDCS improves early Alzheimer’s disease by synaptic vesicle fusion and release. Mil Med Res. 2026;13(1):100003.
DOI：

Zhuang YY, Yan JM, Wu TC, Xu WS, Wu B, Xie X, et al. tDCS improves early Alzheimer’s disease by synaptic vesicle fusion and release. Mil Med Res. 2026;13(1):100003. DOI： 10.1016/j.mmr.2026.100003.

摘要

Abstract

Background:

Working memory deficits

one of the earliest hallmarks of Alzheimer’s disease (AD)

are closely linked to abnormal neural activity in the dorsolateral prefrontal cortex (DLPFC). Transcranial direct current stimulation(tDCS)

a non-invasive neuromodulation therapy

has been shown to ameliorate early AD working memory deficits by modulating excitatory activity in the DLPFC

yet the underlying mechanisms remain incompletely understood.

Methods:

This investigation was structured around three experimental phases. We initially applied tDCS to stimulate the left prefrontal cortex (PFC) of transgenic mice with 5 familial AD (5×FAD) 5 d per week for 4 weeks. Subsequently

we employed optogenetic (Opt) techniques to modulate left PFC glutamatergic neurons. Finally

we inhibited soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) expression in the left PFC to elucidate the essential function of SNARE complex assembly with chaperone molecules in orchestrating synaptic vesicle release.

Results:

tDCS treatment improved working memory deficits in early-stage AD mice. This was accompanied by increased cerebral blood flow

enhanced neuronal excitability

amelioration of neurochemical metabolic disorders

and reduced amyloid β-protein (Aβ) deposition in the left PFC. Opt stimulation of PFC glutamatergic neurons similarly improved working memory

indicating the association between tDCS’s therapeutic effects and synaptic plasticity of excitatory neurons. Crucially

tDCS facilitated synaptic vesicle fusion and release

evidenced by increased vesicle numbers

enhanced release probability

improved synaptic transmission efficacy

and upregulation of the SNARE complex

Snap25

and Syt1. Inhibiting SNARE expression in the left PFC attenuated the tDCS-induced improvements in synaptic vesicle release and working memory.

Conclusion:

These findings collectively demonstrate that left PFC-targeted tDCS modulates interactions between the SNARE complex and chaperone molecules

thereby promoting synaptic vesicle fusion and release. This mechanism underlies the amelioration of early AD-like working memory impairment by tDCS.

关键词

Keywords

references

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