Cholinesterase Inhibitor Reveals Synergistic Potential for Neural Stem Cell-Based Therapy in the 5xFAD Mouse Model of Alzheimer’s Disease

Cheng-Chun Wu,1,2,* Yung-Kuo Lee,3,* Jui-Kang Tsai,4 Yu-Ting Su,5 Yu-Cheng Ho,2 Tian-Huei Chu,3 Kuang-Ti Chen,6,7 Chen-Lin Chang,3,4 Jui-Shen Chen1,8 1Graduate Institute of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan; 2School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan; 3Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan; 4Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan; 5Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City, Taiwan; 6School of Medicine, College of Medicine, China Medical University, Taichung City, Taiwan; 7Department of Veterinary Medicine, Nation Chung-Hsing University, Taichung City, Taiwan; 8Department of Neurosurgery, E-DA Hospital, I-Shou University, Kaohsiung City, Taiwan*These authors contributed equally to this workCorrespondence: Chen-Lin Chang, Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, No. 2, Zhongzheng 1st Road, Lingya Dist, Kaohsiung, 802301, Taiwan, Tel +886-7-7496751-726528, Fax +886-7-7496751, Email [email protected] Jui-Shen Chen, Department of Neurosurgery, E-DA Hospital, I-Shou University, No. 1, E-Da Road, Yan-Cao Dist, Kaohsiung, 824005, Taiwan, Tel +886-7-6151100-7963, Fax +886-7-6151100, Email [email protected] and Objectives: Stem cell therapy shows great promise for treating Alzheimer’s disease (AD). Cholinesterase inhibitors (ChEIs) like donepezil are well-established for alleviating AD symptoms. This study aimed to determine if combining ChEI treatment with stem cell therapy could improve therapeutic outcomes.Methods: Neural stem cells (NSCs) were injected into the hippocampus of the 5xFAD AD mice using a stereotactic technique. Following this, donepezil or a placebo was administered for one month. We assessed behavioral improvements, survival and health of the grafts, and changes in synaptic density.Results: The AD mice demonstrated cognitive impairment in both the Morris water maze and novel object recognition tests. In groups receiving stem cell therapy, donepezil enhanced the survival and neuronal differentiation of grafted NSCs, promoting the establishment of synaptic connections with the host brain. The combined treatment with donepezil and NSC transplantation more effectively increased synaptic density and improved behavioral performance in AD mice compared to NSC transplantation alone.Conclusion: Combining ChEIs with NSC transplantation produces synergistic effects in AD treatment. This approach highlights the potential of integrating these therapies to develop more effective strategies for managing Alzheimer’s disease.Keywords: Alzheimer’s disease, cholinesterase inhibitors, donepezil, neural stem cells, transplantation