{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:52:27Z","timestamp":1792511547544,"version":"4.5.0"},"reference-count":52,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Ministry of Health &amp; Welfare, Republic of Korea","doi-asserted-by":"publisher","award":["HI22C1650"],"award-info":[{"award-number":["HI22C1650"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is one of the most common neurodegenerative diseases. In AD patients, amyloid-\u03b2 (A\u03b2) peptide-mediated degeneration of the cholinergic system utilizing acetylcholine (ACh) for memory acquisition is observed. Since AD therapy using acetylcholinesterase (AChE) inhibitors are only palliative for memory deficits without reversing disease progress, there is a need for effective therapies, and cell-based therapeutic approaches should fulfil this requirement. We established F3.ChAT human neural stem cells (NSCs) encoding the choline acetyltransferase (ChAT) gene, an ACh-synthesizing enzyme, HMO6.NEP human microglial cells encoding the neprilysin (NEP) gene, an A\u03b2-degrading enzyme, and HMO6.SRA cells encoding the scavenger receptor A (SRA) gene, an A\u03b2-uptaking receptor. For the efficacy evaluation of the cells, first, we established an appropriate animal model based on A\u03b2 accumulation and cognitive dysfunction. Among various AD models, intracerebroventricular (ICV) injection of ethylcholine mustard azirinium ion (AF64A) induced the most severe A\u03b2 accumulation and memory dysfunction. Established NSCs and HMO6 cells were transplanted ICV to mice showing memory loss induced by AF64A challenge, and brain A\u03b2 accumulation, ACh concentration and cognitive function were analyzed. All the transplanted F3.ChAT, HMO6.NEP and HMO6.SRA cells were found to survive up to 4 weeks in the mouse brain and expressed their functional genes. Combinational treatment with the NSCs (F3.ChAT) and microglial cells encoding each functional gene (HMO6.NEP or HMO6.SRA) synergistically restored the learning and memory function of AF64A-challenged mice by eliminating A\u03b2 deposits and recovering ACh level. The cells also attenuated inflammatory astrocytic (glial fibrillary acidic protein) response by reducing A\u03b2 accumulation. Taken together, it is expected that NSCs and microglial cells over-expressing ChAT, NEP or SRA genes could be strategies for replacement cell therapy of AD.<\/jats:p>","DOI":"10.3390\/ijms24119561","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T03:06:00Z","timestamp":1685588760000},"page":"9561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Effectiveness of Combinational Treatments for Alzheimer\u2019s Disease with Human Neural Stem Cells and Microglial Cells Over-Expressing Functional Genes"],"prefix":"10.3390","volume":"24","author":[{"given":"Young-Hwan","family":"Ban","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biology Education, Korea National University of Education, Cheongju 28173, Chungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehn-Kyoung","family":"Choi","sequence":"additional","affiliation":[{"name":"Central Research Institute, Designed Cells Co., Ltd., Cheongju 28576, Chungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Myoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Central Research Institute, Designed Cells Co., Ltd., Cheongju 28576, Chungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3449-0645","authenticated-orcid":false,"given":"Seong Soo","family":"Joo","sequence":"additional","affiliation":[{"name":"College of Life Science, Gangneung-Wonju National University, Gangneung 25457, Gangwon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1340-041X","authenticated-orcid":false,"given":"Yun-Bae","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, Republic of Korea"},{"name":"Department of Biology Education, Korea National University of Education, Cheongju 28173, Chungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.pharep.2014.09.004","article-title":"A review on Alzheimer\u2019s disease pathophysiology and its management: An update","volume":"67","author":"Kumar","year":"2015","journal-title":"Pharmacol. 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