Abstract:
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.
journal_name
Stem Cell Res Therjournal_title
Stem cell research & therapyauthors
Blurton-Jones M,Spencer B,Michael S,Castello NA,Agazaryan AA,Davis JL,Müller FJ,Loring JF,Masliah E,LaFerla FMdoi
10.1186/scrt440subject
Has Abstractpub_date
2014-04-16 00:00:00pages
46issue
2issn
1757-6512pii
scrt440journal_volume
5pub_type
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journal_title:Stem cell research & therapy
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journal_title:Stem cell research & therapy
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journal_title:Stem cell research & therapy
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journal_title:Stem cell research & therapy
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