title: Cellular and molecular mechanisms of the restoration of human APP transgenic mouse cognitive dysfunction after transplant of human iPS cell-derived neural cells.
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.
authors.affiliation: Department of Immunology and Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Naruyoshi
authors.initials: N
authors.lastname: Fujiwara
authors.affiliation: Department of Immunology and Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Shimizu
authors.affiliation: Department of Immunology and Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takai
authors.affiliation: Department of Immunology and Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Nagisa
authors.initials: N
authors.lastname: Arimitsu
authors.affiliation: Department of Immunology and Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Immunology and Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Sueshige
authors.initials: S
authors.lastname: Wakisaka
authors.affiliation: Department of Immunology and Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Immunology and Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan. Electronic address: n3suzuki@marianna-u.ac.jp.
authors.forename: Noboru
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003072:Cognition Disorders / Q000235:genetics* / Q000601:surgery*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D033581:Stem Cell Transplantation; D013997:Time Factors; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D018079:Receptors, GABA; C118623:Slc32a1 protein, rat; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002795:Choline O-Acetyltransferase; D051058:Oncogene Protein v-akt
keywords: Cholinergic neuron; Dementia; GABAergic neuron; Human iPS; Nerve regeneration; Transplantation