title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Lilja
authors.affiliation: 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.
authors.forename: Linn
authors.initials: L
authors.lastname: Malmsten
authors.affiliation: 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.
authors.forename: Jennie
authors.initials: J
authors.lastname: Röjdner
authors.affiliation: 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.
authors.forename: Larysa
authors.initials: L
authors.lastname: Voytenko
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, UK.
authors.forename: Alexei
authors.initials: A
authors.lastname: Verkhratsky
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, UK ; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Sven Ove
authors.initials: SO
authors.lastname: Ögren
authors.affiliation: 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 ; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 57 Huddinge, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
authors.affiliation: 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.
authors.forename: Amelia
authors.initials: A
authors.lastname: Marutle
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000523:psychology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology; D049109:Cell Proliferation; D003071:Cognition; D000089662:Doublecortin Protein; D005260:Female; D006624:Hippocampus / Q000601:surgery; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D009416:Nerve Regeneration; D058953:Neural Stem Cells / Q000637:transplantation*; D055495:Neurogenesis; D018722:Nicotinic Agonists / Q000494:pharmacology; D010830:Physostigmine / Q000031:analogs & derivatives / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D033581:Stem Cell Transplantation; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: C520400:(S)-(1-azabicyclo(2.2.2)oct-3-yl)carbamic acid (S)-1-(2-fluorophenyl) ethyl ester; D016229:Amyloid beta-Peptides; D002219:Carbamates; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D018722:Nicotinic Agonists; D011812:Quinuclidines; D064569:alpha7 Nicotinic Acetylcholine Receptor; D010830:Physostigmine; C092280:phenserine