Dataset Information

Human Neural Stem Cells Reinforce Hippocampal Synaptic Network and Rescue Cognitive Deficits in a Mouse Model of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is characterized by memory impairments in its earliest clinical phase. The synaptic loss and dysfunction leading to failures of synaptic networks in AD brain directly cause cognitive deficits of patient. However, it remains unclear whether the synaptic networks in AD brain could be repaired. In this study, we generated functional human induced neural progenitor/stem cells (iNPCs) that had been transplanted into the hippocampus of immunodeficient wild-type and AD mice. The grafted human iNPCs efficiently differentiated into neurons that displayed long-term survival, progressively acquired mature membrane properties, formed graft-host synaptic connections with mouse neurons and functionally integrated into local synaptic circuits, which eventually reinforced and repaired the neural networks of host hippocampus. Consequently, AD mice with human iNPCs exhibited enhanced synaptic plasticity and improved cognitive abilities. Together, our results suggest that restoring synaptic failures by stem cells might provide new directions for the development of novel treatments for human AD.

SUBMITTER: Zhang T

PROVIDER: S-EPMC6915849 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Human Neural Stem Cells Reinforce Hippocampal Synaptic Network and Rescue Cognitive Deficits in a Mouse Model of Alzheimer's Disease.

Zhang Ting T Ke Wei W Zhou Xuan X Qian Yun Y Feng Su S Wang Ran R Cui Guizhong G Tao Ran R Guo Wenke W Duan Yanhong Y Zhang Xiaobing X Cao Xiaohua X Shu Yousheng Y Yue Chunmei C Jing Naihe N

Stem cell reports 20191121 6

Alzheimer's disease (AD) is characterized by memory impairments in its earliest clinical phase. The synaptic loss and dysfunction leading to failures of synaptic networks in AD brain directly cause cognitive deficits of patient. However, it remains unclear whether the synaptic networks in AD brain could be repaired. In this study, we generated functional human induced neural progenitor/stem cells (iNPCs) that had been transplanted into the hippocampus of immunodeficient wild-type and AD mice. Th ...[more]

PMID: 31761676

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Project description:BackgroundRibosomal protein S6 kinase 1 (S6K1) is a serine-threonine kinase that has two main isoforms: p70S6K (70-kDa isoform) and p85S6K (85-kDa isoform). p70S6K, with its upstream mammalian target of rapamycin (mTOR), has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer's disease (AD). However, the function of p85S6K has long been neglected due to its high similarity to p70S6k. The role of p85S6K in learning and memory is still largely unknown.MethodsWe fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K. Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor. The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence, Western blot, in situ proximity ligation assay, morphological staining and behavioral examination. Further, the expression level of p85S6K was measured in brains from AD patients and AD model mice.Resultsp85S6K, but not p70S6K, was enriched in the postsynaptic densities. Moreover, knockdown of p85S6K resulted in defective spatial and recognition memory. In addition, p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150. Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in synapses, thus sustaining synaptic function and spine densities. Moreover, p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice. Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice.ConclusionsThese results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1. The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.

Dataset Information

Human Neural Stem Cells Reinforce Hippocampal Synaptic Network and Rescue Cognitive Deficits in a Mouse Model of Alzheimer's Disease.

Publications

Human Neural Stem Cells Reinforce Hippocampal Synaptic Network and Rescue Cognitive Deficits in a Mouse Model of Alzheimer's Disease.

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