title: Human neural stem cells alleviate Alzheimer-like pathology in a mouse model.
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.
authors: Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, South Korea. sunew@yuhs.ac.
authors: Il-Shin
authors: IS
authors: Lee
authors: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, South Korea. aslk82@yuhs.ac.
authors: Kwangsoo
authors: K
authors: Jung
authors: Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, South Korea. whitesnown7@yuhs.ac.
authors: Il-Sun
authors: IS
authors: Kim
authors: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, South Korea. ulise@yuhs.ac.
authors: Haejin
authors: H
authors: Lee
authors: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, South Korea. mrfpno@yuhs.ac.
authors: Miri
authors: M
authors: Kim
authors: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, South Korea. yuntoby@yuhs.ac.
authors: Seokhwan
authors: S
authors: Yun
authors: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, South Korea. jin8140@yuhs.ac.
authors: Kyujin
authors: K
authors: Hwang
authors: Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, South Korea. golden-week@yuhs.ac.
authors: Jeong Eun
authors: JE
authors: Shin
authors: Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, South Korea. kipark@yuhs.ac.|Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 120-752, South Korea. kipark@yuhs.ac.
authors: Kook In
authors: KI
authors: Park
mesh_terms: D000544:Alzheimer Disease / Q000628:therapy*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D019070:Cell Lineage; D002465:Cell Movement; D004195:Disease Models, Animal; D016332:Fetal Tissue Transplantation; D005865:Gestational Age; D005911:Gliosis / Q000517:prevention & control; D006085:Graft Survival; D064593:Heterografts; D006801:Humans; D020547:Lateral Ventricles; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D058953:Neural Stem Cells / Q000637:transplantation*; D010446:Peptide Fragments / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D010766:Phosphorylation; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D065852:Spatial Memory; D013687:Telencephalon / Q000166:cytology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C558298:Mapt protein, mouse; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D010751:Phosphopyruvate Hydratase