RRC ID 37594
Author Fujiwara N, Shimizu J, Takai K, Arimitsu N, Ueda Y, Wakisaka S, Suzuki T, Suzuki N.
Title Cellular and molecular mechanisms of the restoration of human APP transgenic mouse cognitive dysfunction after transplant of human iPS cell-derived neural cells.
Journal Exp. Neurol.
Abstract Cholinergic neuronal loss is a common finding in patients with Alzheimer's disease (AD) and AD model mice. We previously transplanted neurons derived from human induced pluripotent stem (iPS) cells into the hippocampus of human amyloid precursor protein transgenic AD model mice. In the present study, we examined the cellular and molecular mechanisms involved in the alleviation of cognitive dysfunction in transplanted mice. After transplant, mice showed improvement in cognitive function, confirming our previous findings. Human choline acetyltransferase (ChAT)-positive cholinergic neurons were distributed throughout the cortex of the grafted mice. Human and mouse ChAT-positive neurons and alpha7 nicotinic acetylcholine receptor (α7nAChR)-positive neurons were significantly increased in the cortex and hippocampus of the grafted mice compared with the vehicle-injected mice. In addition, human and mouse vesicular GABA transporter (VGAT)-positive neurons were located mainly in the hippocampus and, though the number was small, human VGAT-positive neurons were observed in the cortex. In the grafted mouse cortex, the number of GABA receptor (GABAR)-positive neurons of both human origin and mouse origin were significantly increased compared with those in the vehicle-injected mouse cortex. The α7nAChR-positive and GABAR-positive neurons expressed phosphorylated Akt and c-fos in the cortex, suggesting that these receptor-expressing neurons were possibly activated by the neurotransmitters secreted from the grafted neurons. Collectively, the grafted and host neurons may form positive feedback loops via neurotransmitter secretion in both the cerebral cortex and hippocampus, leading to alleviation of cognitive dysfunction in dementia model mice.
Volume 271
Pages 423-31
Published 2015-9
DOI 10.1016/j.expneurol.2015.07.008
PII S0014-4886(15)30041-8
PMID 26196079
MeSH Amyloid beta-Protein Precursor / genetics* Animals Choline O-Acetyltransferase / metabolism Cognition Disorders / genetics* Cognition Disorders / surgery* Disease Models, Animal Gene Expression Regulation / physiology Humans Induced Pluripotent Stem Cells / physiology* Maze Learning Mice Mice, Transgenic Nerve Tissue Proteins / metabolism Neurons / metabolism Neurons / physiology* Oncogene Protein v-akt / metabolism Receptors, GABA / metabolism Recovery of Function / physiology* Stem Cell Transplantation* Time Factors Vesicular Inhibitory Amino Acid Transport Proteins / metabolism alpha7 Nicotinic Acetylcholine Receptor / metabolism
IF 4.483
Times Cited 4
Human and Animal Cells 201B7(HPS0063) 253G1(HPS0002)