title: Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer's Disease by Enhancing Neuronal Connectivity and Metabolic Activity.
abstract: Alzheimer's disease (AD), the most frequent type of dementia, is featured by Aβ pathology, neural degeneration and cognitive decline. To date, there is no cure for this disease. Neural stem cell (NSC) transplantation provides new promise for treating AD. Many studies report that intra-hippocampal transplantation of murine NSCs improved cognition in rodents with AD by alleviating neurodegeneration via neuronal complement or replacement. However, few reports examined the potential of human NSC transplantation for AD. In this study, we implanted human brain-derived NSCs (hNSCs) into bilateral hippocampus of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mouse model of AD to test the effects of hNSC transplantation on Alzheimer's behavior and neuropathology. Six weeks later, transplanted hNSCs engrafted into the brains of AD mice, migrated dispersedly in broad brain regions, and some of them differentiated into neural cell types of central nervous system (CNS). The hNSC transplantation restored the recognition, learning and memory deficits but not anxiety tasks in AD mice. Although Aβ plaques were not significantly reduced, the neuronal, synaptic and nerve fiber density was significantly increased in the frontal cortex and hippocampus of hNSC-treated AD mice, suggesting of improved neuronal connectivity in AD brains after hNSC transplantation. Ultrastructural analysis confirmed that synapses and nerve fibers maintained relatively well-structured shapes in these mice. Furthermore,in vivomagnetic resonance spectroscopy (MRS) showed that hNSC-treated mice had notably increased levels of N-acetylaspartate (NAA) and Glu in the frontal cortex and hippocampus, suggesting that neuronal metabolic activity was improved in AD brains after hNSC transplantation. These results suggest that transplanted hNSCs rescued Alzheimer's cognition by enhancing neuronal connectivity and metabolic activity through a compensation mechanism in APP/PS1 mice. This study provides preclinical evidence that hNSC transplantation can be a possible and feasible strategy for treating patients with AD.
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, China.
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, Comparative Medical Center, Peking Union Medical College and Institute of Laboratory Animal Science, Chinese Academy of Medical Science Beijing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Center for Stem Cell Biology and Regenerative Medicine, Center for Life Sciences, School of Medicine, Tsinghua University Beijing, China.
authors.forename: Xicai
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, China.
authors.forename: Fuxing
authors.initials: F
authors.lastname: Zuo
authors.affiliation: Center for Medical Experiments and Testing, Capital Medical University Beijing, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lei
authors.affiliation: Center for Stem Cell Biology and Regenerative Medicine, Center for Life Sciences, School of Medicine, Tsinghua University Beijing, China.
authors.forename: Zhanjing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, China.
authors.forename: Xinjie
authors.initials: X
authors.lastname: Bao
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, China.
authors.forename: Renzhi
authors.initials: R
authors.lastname: Wang
keywords: APP/PS1 mice; Alzheimer’s disease; cognition; human neural stem cell; metabolic activity; neuronal connectivity