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

• Published in: International journal of molecular sciences Vol. 21; no. 11; p. 3958
• Main Authors: Park, Dongsun, Choi, Ehn-Kyoung, Cho, Tai-Hyoung, Joo, Seong Soo, Kim, Yun-Bae
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31.05.2020; MDPI
• Subjects: acetylcholine; Acetylcholine - biosynthesis; Acetylcholinesterase; Acetyltransferase; Alzheimer disease; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Animal cognition; Animal models; Animals; Astrocytes; Astrocytes - metabolism; Aβ deposition; Brain - metabolism; Cell Proliferation; Cell therapy; Cell- and Tissue-Based Therapy; Choline; choline acetyltransferase; Choline O-acetyltransferase; Choline O-Acetyltransferase - metabolism; Cholinergic transmission; Cholinergics; Cognition; Cognition Disorders - therapy; Cognitive ability; Cytokines; Degeneration; Disease; Enzymes; Genes; Growth factors; Hippocampus - metabolism; human neural stem cell; Humans; Inflammation; Memory; Memory Disorders - metabolism; Mice; Mice, Transgenic; Microglia - metabolism; Neprilysin; Nerve Growth Factors - metabolism; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurodegeneration; Neurons - metabolism; neuroregeneration; Neurotrophic factors; Peptides; Physical activity; Presenilin-1 - genetics; Proteins; Receptors, Cholinergic - metabolism; Recovery of function; Regeneration; Secretase; Stem cell transplantation; Stem cells; Transplantation; human neural stem cell; choline acetyltransferase; Aβ deposition; acetylcholine; Alzheimer disease; neuroregeneration
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21113958

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.