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

编码 ChAT 基因的人神经干细胞通过乙酰胆碱合成恢复认知功能,A β 消除,和 APPswe / PS1dE9 小鼠的神经再生。

• 影响指数: 6.208
• 发表时间: May 2020 31
• 来源期刊: Int J Mol Sci
• DOI: 10.3390/ijms21113958
• PMID: 32486466
• 文章类型: Journal Article
• 中科院分区: Q2
• 方向: 生物
• 作者列表: Park D,Choi EK,Cho TH,Joo SS,Kim YB

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

Mesh: Acetylcholine / biosynthesis; Amyloid beta-Peptides / metabolism; Amyloid beta-Protein Precursor / genetics; Animals; Astrocytes / metabolism; Brain / metabolism; Cell Proliferation; Cell- and Tissue-Based Therapy; Choline O-Acetyltransferase / metabolism; Cognition; Cognition Disorders / therapy; Hippocampus / metabolism; Humans; Memory Disorders / metabolism; Mice; Mice, Transgenic; Microglia / metabolism; Nerve Growth Factors / metabolism; Neural Stem Cells / cytology metabolism; Neurons / metabolism; Presenilin-1 / genetics; Receptors, Cholinergic / metabolism; Regeneration

Abstract

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.

摘要

在阿尔茨海默病（AD）患者中，观察到利用乙酰胆碱进行记忆获取的胆碱能系统退化。由于使用乙酰胆碱酯酶（AChE）抑制剂的AD治疗仅可缓解记忆缺陷，而不会减缓或逆转疾病进展，需要有效的治疗方法，而针对AD的基于干细胞的治疗方法应满足这一要求。我们建立了一个编码胆碱乙酰转移酶（ChAT）基因的人神经干细胞（NSC）系，乙酰胆碱合成酶。APPswe/PS1dE9AD模子小鼠移植了F3。ChATNSC表现出改善的认知功能和身体活动。移植F3。AD小鼠ChAT神经干细胞分化为神经元和星形胶质细胞,产生的ChAT蛋白，提高了ACH水平，提高了学习和记忆功能。F3.ChAT细胞移植通过恢复小胶质细胞功能来减少Aβ沉积；即β分泌酶和炎性细胞因子的下调和Aβ降解酶脑啡肽酶的上调。F3.ChAT细胞恢复生长因子（GFs）和神经营养因子（NFs），它们诱导宿主大脑中神经干细胞的增殖。这些发现表明过度表达ChAT的神经干细胞可以通过释放ACh来改善AD动物的复杂认知和身体缺陷。减少Aβ沉积，并通过产生GFs/NFs促进神经再生。提示过表达ChAT的NSC可能是晚期AD治疗中细胞治疗的候选物。