Title : Effectiveness of Combinational Treatments for Alzheimer's Disease with Human Neural Stem Cells and Microglial Cells Over-Expressing Functional Genes - Ban_2023_Int.J.Mol.Sci_24_ |
Author(s) : Ban YH , Park D , Choi EK , Kim TM , Joo SS , Kim YB |
Ref : Int J Mol Sci , 24 : , 2023 |
Abstract :
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. In AD patients, amyloid-beta (Abeta) 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 Abeta-degrading enzyme, and HMO6.SRA cells encoding the scavenger receptor A (SRA) gene, an Abeta-uptaking receptor. For the efficacy evaluation of the cells, first, we established an appropriate animal model based on Abeta accumulation and cognitive dysfunction. Among various AD models, intracerebroventricular (ICV) injection of ethylcholine mustard azirinium ion (AF64A) induced the most severe Abeta accumulation and memory dysfunction. Established NSCs and HMO6 cells were transplanted ICV to mice showing memory loss induced by AF64A challenge, and brain Abeta 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 Abeta deposits and recovering ACh level. The cells also attenuated inflammatory astrocytic (glial fibrillary acidic protein) response by reducing Abeta 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. |
PubMedSearch : Ban_2023_Int.J.Mol.Sci_24_ |
PubMedID: 37298510 |
Ban YH, Park D, Choi EK, Kim TM, Joo SS, Kim YB (2023)
Effectiveness of Combinational Treatments for Alzheimer's Disease with Human Neural Stem Cells and Microglial Cells Over-Expressing Functional Genes
Int J Mol Sci
24 :
Ban YH, Park D, Choi EK, Kim TM, Joo SS, Kim YB (2023)
Int J Mol Sci
24 :