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Published July 15, 2015 | Version v1
Journal article Open

Neural Stem Cell Transplant-Induced Effect on Neurogenesis and Cognition in Alzheimer Tg2576 Mice Is Inhibited by Concomitant Treatment with Amyloid-Lowering or Cholinergic α7 Nicotinic Receptor Drugs.

  • 1. Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 57 Huddinge, Sweden
  • 2. Faculty of Life Sciences,The University of Manchester, Manchester M13 9PT, UK
  • 3. Faculty of Life Sciences,The University of Manchester, Manchester M13 9PT, UK and Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
  • 4. Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 57 Huddinge, Sweden and Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 57 Huddinge, Sweden

Description

Stimulating regeneration in the brain has the potential to rescue neuronal networks and counteract progressive pathological changes in Alzheimer's disease (AD). This study investigated whether drugs with different mechanisms of action could enhance neurogenesis and improve cognition in mice receiving human neural stem cell (hNSC) transplants. Six- to nine-month-old AD Tg2576 mice were treated for five weeks with the amyloid-modulatory and neurotrophic drug (+)-phenserine or with the partial α7 nicotinic receptor (nAChR) agonist JN403, combined with bilateral intrahippocampal hNSC transplantation. We observed improved spatial memory in hNSC-transplanted non-drug-treated Tg2576 mice but not in those receiving drugs, and this was accompanied by an increased number of Doublecortin- (DCX-) positive cells in the dentate gyrus, a surrogate marker for newly generated neurons. Treatment with (+)-phenserine did however improve graft survival in the hippocampus. An accumulation of α7 nAChR-expressing astrocytes was observed around the injection site, suggesting their involvement in repair and scarring processes. Interestingly, JN403 treatment decreased the number of α7 nAChR-expressing astrocytes, correlating with a reduction in the number of DCX-positive cells in the dentate gyrus. We conclude that transplanting hNSCs enhances endogenous neurogenesis and prevents further cognitive deterioration in Tg2576 mice, while simultaneous treatments with (+)-phenserine or JN403 result in countertherapeutic effects.

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Funding

INMIND – Imaging of Neuroinflammation in Neurodegenerative Diseases 278850
European Commission