Human Neural Stem Cells Encoding ChAT Gene Restore Cognitive Function via Acetylcholine Synthesis, Aβ Elimination, and Neuroregeneration in APPswe/PS1dE9 Mice

International Journal of Molecular Sciences

Yun-Bae Kim¹  Ehn-Kyoung Choi¹  Dongsun Park²  SeongSoo Joo³  Tai-Hyoung Cho⁴ 

[1] Central Research Institute, Designed Cells Co., Ltd., Cheongju, Chungbuk 28576, Korea;Department of Biology Education, Korea National University of Education, Cheongju, Chungbuk 29173, Korea;Department of Marine Molecular Biotechnology, Gangneung-Wonju National University, Gangneung, Gangwon 25457, Korea;Department of Neurosurgery, Korea University College of Medicine, Korea University Anam Hospital, Seoul 02841, Korea;

关键词: Alzheimer disease;    human neural stem cell;    choline acetyltransferase;    acetylcholine;    Aβ deposition;    neuroregeneration;   

DOI  :  10.3390/ijms21113958

来源: DOAJ

【 摘 要 】

In Alzheimer disease (AD) patients, degeneration of the cholinergic system utilizing acetylcholine for memory acquisition is observed. Since AD therapy using acetylcholinesterase (AChE) inhibitors are only palliative for memory deficits without slowing or reversing disease progress, there is a need for effective therapies, and stem cell-based therapeutic approaches targeting AD should fulfill this requirement. We established a human neural stem cell (NSC) line encoding choline acetyltransferase (ChAT) gene, an acetylcholine-synthesizing enzyme. APPswe/PS1dE9 AD model mice transplanted with the F3.ChAT NSCs exhibited improved cognitive function and physical activity. Transplanted F3.ChAT NSCs in the AD mice differentiated into neurons and astrocytes, produced ChAT protein, increased the ACh level, and improved the learning and memory function. F3.ChAT cell transplantation reduced Aβ deposits by recovering microglial function; i.e., the down-regulation of β-secretase and inflammatory cytokines and up-regulation of Aβ-degrading enzyme neprilysin. F3.ChAT cells restored growth factors (GFs) and neurotrophic factors (NFs), and they induced the proliferation of NSCs in the host brain. These findings indicate that NSCs overexpressing ChAT can ameliorate complex cognitive and physical deficits of AD animals by releasing ACh, reducing Aβ deposit, and promoting neuroregeneration by the production of GFs/NFs. It is suggested that NSCs overexpressing ChAT could be a candidate for cell therapy in advanced AD therapy.

【 授权许可】

Unknown