Neural Stem Cells Improve Memory in an Inducible Mouse Model of Neuronal Loss

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2007; 27(44):11925-33. DOI: 10.1523/JNEUROSCI.1627-07.2007
Source: PubMed


Neuronal loss is a major pathological outcome of many common neurological disorders, including ischemia, traumatic brain injury, and Alzheimer disease. Stem cell-based approaches have received considerable attention as a potential means of treatment, although it remains to be determined whether stem cells can ameliorate memory dysfunction, a devastating component of these disorders. We generated a transgenic mouse model in which the tetracycline-off system is used to regulate expression of diphtheria toxin A chain. After induction, we find progressive neuronal loss primarily within the hippocampus, leading to specific impairments in memory. We find that neural stem cells transplanted into the brain after neuronal ablation survive, migrate, differentiate and, most significantly, improve memory. These results show that stem cells may have therapeutic value in diseases and conditions that result in memory loss.

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    • "To study the adaptive response of the hippocampus following neuronal loss, we used the innovative CaM/Tet-DTA mouse model that induces hippocampal neuronal loss [32], [33]. This double transgene system consists of a transactivator driven by a constitutively active CaM-KII-alpha promoter, which in turns drive expression of a diphtheria toxin. "
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    ABSTRACT: Neuronal loss is a common component of a variety of neurodegenerative disorders (including Alzheimer's, Parkinson's, and Huntington's disease) and brain traumas (stroke, epilepsy, and traumatic brain injury). One brain region that commonly exhibits neuronal loss in several neurodegenerative disorders is the hippocampus, an area of the brain critical for the formation and retrieval of memories. Long-lasting and sometimes unrecoverable deficits caused by neuronal loss present a unique challenge for clinicians and for researchers who attempt to model these traumas in animals. Can these deficits be recovered, and if so, is the brain capable of regeneration following neuronal loss? To address this significant question, we utilized the innovative CaM/Tet-DTA mouse model that selectively induces neuronal ablation. We found that we are able to inflict a consistent and significant lesion to the hippocampus, resulting in hippocampally-dependent behavioral deficits and a long-lasting upregulation in neurogenesis, suggesting that this process might be a critical part of hippocampal recovery. In addition, we provide novel evidence of angiogenic and vasculature changes following hippocampal neuronal loss in CaM/Tet-DTA mice. We posit that angiogenesis may be an important factor that promotes neurogenic upregulation following hippocampal neuronal loss, and both factors, angiogenesis and neurogenesis, can contribute to the adaptive response of the brain for behavioral recovery.
    PLoS ONE 09/2014; 9(9). DOI:10.1371/journal.pone.0106009 · 3.23 Impact Factor
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    • "To determine the differentiated phenotype of engrafted cells, double-labeling for GFP and neuronal and glial markers was performed. We previously showed that murine NSCs transplanted into aged brains primarily express astrocytic markers [3,20]. In this study we found similar results, detecting very few NSCs that co-expressed the neuronal marker NeuN (Figure 5F), but large numbers of GFP-expressing cells that co-expressed the astrocyte marker GFAP in both sNEP and control-NSC engrafted sides (Figure 5G-L). "
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    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.
    Stem Cell Research & Therapy 04/2014; 5(2):46. DOI:10.1186/scrt440 · 3.37 Impact Factor
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    • "All procedures were performed with strict adherence to this protocol and all efforts were made to minimize suffering. GFP-expressing CaM/Tet-DTA mice were produced by crossing female, homozygous Tet-DTA mice [20] with a hemizygous Thy1-GFP-M male (Jackson Labs, Bar Harbor, ME, catalog #007788) and interbreeding offspring until homozygosity was reached for both transgenes. The genotype of each animal of each generation was determined for Tet-DTA and Thy1-GFP by Southern blot, as described below. "
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    ABSTRACT: Augmenting BDNF/TrkB signaling has been demonstrated to be a promising strategy for reversing cognitive deficits in preclinical models of Alzheimer disease (AD). Although these studies highlight the potential of targeting BDNF/TrkB signaling, this strategy has not yet been tested in a model that develops the disease features that are most closely associated with cognitive decline in AD: severe synaptic and neuronal loss. In the present study, we investigated the impact of 7,8-dihydroxyflavone (DHF), a TrkB agonist, in CaM/Tet-DTA mice, an inducible model of severe neuronal loss in the hippocampus and cortex. Systemic 7,8-DHF treatment significantly improved spatial memory in lesioned mice, as measured by water maze. Analysis of GFP-labeled neurons in CaM/Tet-DTA mice revealed that 7,8-DHF induced a significant and selective increase in the density of thin spines in CA1 of lesioned mice, without affecting mushroom or stubby spines. These findings suggest chronic upregulation of TrkB signaling with 7,8-DHF may be an effective and practical strategy for improving function in AD, even after substantial neuronal loss has occurred.
    PLoS ONE 03/2014; 9(3):e91453. DOI:10.1371/journal.pone.0091453 · 3.23 Impact Factor
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