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

Dongsun Park,Seong Soo Joo,Yun-Bae Kim,Tai-Hyoung Cho,Ehn-Kyoung Choi

doi:10.3390/ijms21113958

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.

Highlights

Alzheimer disease (AD) is a progressive neurodegenerative disease, which is characterized by degeneration and the loss of neurons and synapses throughout the brain
Four weeks after intracerebroventricular (ICV) transplantation of neural stem cell (NSC) (106 cells/mouse) into the brain of APPswe/PS1dE9 Tg mice, transplanted F3 and F3.choline acetyltransferase (ChAT) human NSCs were detected in the hippocampus and cortex
Both F3 (Figure 1A) and F3.ChAT (Figure 1B) NSCs were found to differentiate into neurons (NF-H-positive) and in part into astrocytes (GFAP-positive) in the brain microenvironment, and they produced ChAT protein

Summary

Introduction

Alzheimer disease (AD) is a progressive neurodegenerative disease, which is characterized by degeneration and the loss of neurons and synapses throughout the brain. For AD therapy, the administration of acetylcholinesterase (AChE) inhibitors partially recovers cognitive deficits [3]. Since these drugs are only palliative without slowing or reversing disease progress, there is a need for effective therapies for patients with AD, and stem cell-based therapeutic approaches targeting AD should fulfill this requirement. As an animal model of human AD, APPswe/PS1dE9 transgenic (Tg) mice are characterized by amyloid β (Aβ) plaques, neurofibillary tangles, and extensive inflammation leading to ACh depletion and learning and memory impairments [4]. In APPswe/PS1dE9 mice, functional changes of microglia; i.e, the up-regulation of Aβ-producing systems (cytokines and β-secretase) and down-regulation of Aβ-clearing machinery (scavenger receptors and degrading enzymes such as neprilysin) play a key role for accumulation of neurotoxic Aβ peptides [5]

Methods

Results

Conclusion