1. Human neural stem cells alleviate Alzheimer-like pathology in a mouse model
- Author
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Il Sun Kim, Seokhwan Yun, Haejin Lee, Il Shin Lee, Kwangsoo Jung, Kook In Park, Kyujin Hwang, Jeong Eun Shin, and Miri Kim
- Subjects
Telencephalon ,Pathology ,Human neural stem cells ,Microgliosis ,Mice ,Neural Stem Cells ,Cell Movement ,Lateral Ventricles ,Aspartic Acid Endopeptidases ,Glycogen synthase kinase 3β (GSK3β) ,Gliosis ,Phosphorylation ,Alzheimer's disease ,Transplantation ,Trophicfactors ,Glycogen synthase kinase 3 beta (GSK3 beta) ,Anti-inflammation ,Spatial Memory ,Microglia ,Graft Survival ,Neural stem cell ,Astrogliosis ,medicine.anatomical_structure ,Heterografts ,medicine.symptom ,Alzheimer’s disease ,Signal Transduction ,Research Article ,Genetically modified mouse ,medicine.medical_specialty ,Clinical Neurology ,Mutation, Missense ,Inflammation ,Gestational Age ,Mice, Transgenic ,tau Proteins ,Biology ,Cellular and Molecular Neuroscience ,Alzheimer Disease ,Fetal Tissue Transplantation ,Trophic factors ,medicine ,Animals ,Humans ,Point Mutation ,Cell Lineage ,Molecular Biology ,Amyloid beta-Peptides ,medicine.disease ,Peptide Fragments ,Disease Models, Animal ,Phosphopyruvate Hydratase ,Synaptic plasticity ,Neurology (clinical) ,Amyloid Precursor Protein Secretases ,Neuroscience ,Protein Processing, Post-Translational - Abstract
Background Alzheimer’s disease (AD) is an inexorable neurodegenerative disease that commonly occurs in the elderly. The cognitive impairment caused by AD is associated with abnormal accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, which are accompanied by inflammation. Neural stem cells (NSCs) are self-renewing, multipotential cells that differentiate into distinct neural cells. When transplanted into a diseased brain, NSCs repair and replace injured tissues after migration toward and engraftment within lesions. We investigated the therapeutic effects in an AD mouse model of human NSCs (hNSCs) that derived from an aborted human fetal telencephalon at 13 weeks of gestation. Cells were transplanted into the cerebral lateral ventricles of neuron-specific enolase promoter-controlled APPsw-expressing (NSE/APPsw) transgenic mice at 13 months of age. Results Implanted cells extensively migrated and engrafted, and some differentiated into neuronal and glial cells, although most hNSCs remained immature. The hNSC transplantation improved spatial memory in these mice, which also showed decreased tau phosphorylation and Aβ42 levels and attenuated microgliosis and astrogliosis. The hNSC transplantation reduced tau phosphorylation via Trk-dependent Akt/GSK3β signaling, down-regulated Aβ production through an Akt/GSK3β signaling-mediated decrease in BACE1, and decreased expression of inflammatory mediators through deactivation of microglia that was mediated by cell-to-cell contact, secretion of anti-inflammatory factors generated from hNSCs, or both. The hNSC transplantation also facilitated synaptic plasticity and anti-apoptotic function via trophic supplies. Furthermore, the safety and feasibility of hNSC transplantation are supported. Conclusions These findings demonstrate the hNSC transplantation modulates diverse AD pathologies and rescue impaired memory via multiple mechanisms in an AD model. Thus, our data provide tangible preclinical evidence that human NSC transplantation could be a safe and versatile approach for treating AD patients. Electronic supplementary material The online version of this article (doi:10.1186/s13024-015-0035-6) contains supplementary material, which is available to authorized users.
- Published
- 2015