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Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models

INTRODUCTION: Short-term neural stem cell (NSC) transplantation improves cognition in Alzheimer’s disease (AD) transgenic mice by enhancing endogenous synaptic connectivity. However, this approach has no effect on the underlying beta-amyloid (Aβ) and neurofibrillary tangle pathology. Long term effic...

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Autores principales: Blurton-Jones, Mathew, Spencer, Brian, Michael, Sara, Castello, Nicholas A, Agazaryan, Andranik A, Davis, Joy L, Müller, Franz-Josef, Loring, Jeanne F, Masliah, Eliezer, LaFerla, Frank M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055090/
https://www.ncbi.nlm.nih.gov/pubmed/25022790
http://dx.doi.org/10.1186/scrt440
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author Blurton-Jones, Mathew
Spencer, Brian
Michael, Sara
Castello, Nicholas A
Agazaryan, Andranik A
Davis, Joy L
Müller, Franz-Josef
Loring, Jeanne F
Masliah, Eliezer
LaFerla, Frank M
author_facet Blurton-Jones, Mathew
Spencer, Brian
Michael, Sara
Castello, Nicholas A
Agazaryan, Andranik A
Davis, Joy L
Müller, Franz-Josef
Loring, Jeanne F
Masliah, Eliezer
LaFerla, Frank M
author_sort Blurton-Jones, Mathew
collection PubMed
description INTRODUCTION: Short-term neural stem cell (NSC) transplantation improves cognition in Alzheimer’s disease (AD) transgenic mice by enhancing endogenous synaptic connectivity. However, this approach has no effect on the underlying beta-amyloid (Aβ) and neurofibrillary tangle pathology. Long term efficacy of cell based approaches may therefore require combinatorial approaches. METHODS: To begin to examine this question we genetically-modified NSCs to stably express and secrete the Aβ-degrading enzyme, neprilysin (sNEP). Next, we studied the effects of sNEP expression in vitro by quantifying Aβ-degrading activity, NSC multipotency markers, and Aβ-induced toxicity. To determine whether sNEP-expressing NSCs can also modulate AD-pathogenesis in vivo, control-modified and sNEP-NSCs were transplanted unilaterally into the hippocampus of two independent and well characterized transgenic models of AD: 3xTg-AD and Thy1-APP mice. After three months, stem cell engraftment, neprilysin expression, and AD pathology were examined. RESULTS: Our findings reveal that stem cell-mediated delivery of NEP provides marked and significant reductions in Aβ pathology and increases synaptic density in both 3xTg-AD and Thy1-APP transgenic mice. Remarkably, Aβ plaque loads are reduced not only in the hippocampus and subiculum adjacent to engrafted NSCs, but also within the amygdala and medial septum, areas that receive afferent projections from the engrafted region. CONCLUSIONS: Taken together, our data suggest that genetically-modified NSCs could provide a powerful combinatorial approach to not only enhance synaptic plasticity but to also target and modify underlying Alzheimer’s disease pathology.
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spelling pubmed-40550902014-06-13 Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models Blurton-Jones, Mathew Spencer, Brian Michael, Sara Castello, Nicholas A Agazaryan, Andranik A Davis, Joy L Müller, Franz-Josef Loring, Jeanne F Masliah, Eliezer LaFerla, Frank M Stem Cell Res Ther Research INTRODUCTION: Short-term neural stem cell (NSC) transplantation improves cognition in Alzheimer’s disease (AD) transgenic mice by enhancing endogenous synaptic connectivity. However, this approach has no effect on the underlying beta-amyloid (Aβ) and neurofibrillary tangle pathology. Long term efficacy of cell based approaches may therefore require combinatorial approaches. METHODS: To begin to examine this question we genetically-modified NSCs to stably express and secrete the Aβ-degrading enzyme, neprilysin (sNEP). Next, we studied the effects of sNEP expression in vitro by quantifying Aβ-degrading activity, NSC multipotency markers, and Aβ-induced toxicity. To determine whether sNEP-expressing NSCs can also modulate AD-pathogenesis in vivo, control-modified and sNEP-NSCs were transplanted unilaterally into the hippocampus of two independent and well characterized transgenic models of AD: 3xTg-AD and Thy1-APP mice. After three months, stem cell engraftment, neprilysin expression, and AD pathology were examined. RESULTS: Our findings reveal that stem cell-mediated delivery of NEP provides marked and significant reductions in Aβ pathology and increases synaptic density in both 3xTg-AD and Thy1-APP transgenic mice. Remarkably, Aβ plaque loads are reduced not only in the hippocampus and subiculum adjacent to engrafted NSCs, but also within the amygdala and medial septum, areas that receive afferent projections from the engrafted region. CONCLUSIONS: Taken together, our data suggest that genetically-modified NSCs could provide a powerful combinatorial approach to not only enhance synaptic plasticity but to also target and modify underlying Alzheimer’s disease pathology. BioMed Central 2014-04-16 /pmc/articles/PMC4055090/ /pubmed/25022790 http://dx.doi.org/10.1186/scrt440 Text en Copyright © 2014 Blurton-Jones et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Blurton-Jones, Mathew
Spencer, Brian
Michael, Sara
Castello, Nicholas A
Agazaryan, Andranik A
Davis, Joy L
Müller, Franz-Josef
Loring, Jeanne F
Masliah, Eliezer
LaFerla, Frank M
Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models
title Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models
title_full Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models
title_fullStr Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models
title_full_unstemmed Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models
title_short Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models
title_sort neural stem cells genetically-modified to express neprilysin reduce pathology in alzheimer transgenic models
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055090/
https://www.ncbi.nlm.nih.gov/pubmed/25022790
http://dx.doi.org/10.1186/scrt440
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