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S3‐02‐02: Neural Stem cell transplants
Author(s) -
LaFerla Frank
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.2364
Subject(s) - neural stem cell , transplantation , genetically modified mouse , neuroscience , stem cell , transgene , biology , microbiology and biotechnology , medicine , biochemistry , gene
Background: Neural stem cell transplantation represents on unexplained approach for treating neurodegenerative disorders associated with cognitive decline. Short-term neural stem cell transplantation rescues cognition in Alzheimer’s Disease (AD) transgenic mice by enhancing endogenous synaptic connectivity. However, NSCs have no effect on the underlying betaamyloid and neurofibrillary tangle pathologies that drive AD. It is likely that a combinatorial approach will be needed to provide long-term benefits. Methods:Here we genetically-modified murine NSCs to stably express and secrete the Aß-degrading enzyme, neprilysin (sNEP). In vitro examination of sNEP-expressing NSCs confirmed that this approach enhances Aßdegrading activity without altering the multipotent phenotype of NSCs. To determine whether NEP-expressing NSCs can also modulate AD-pathogenesis in vivo, we performed transplantation studies using two independent and well characterized transgenic models of AD: 3xTg-AD and Thy1-APP mice. Results: Aged transgenic mice were transplanted unilaterally with sNEP-NSCs versus control-transfected NSCs. After three months, stem cell engraftment, neprilysin expression, and AD pathology were examined. Our findings reveal that stem cell-mediated delivery of neprilysin provides dramatic and significant reductions in Aß pathology in both 3xTg-AD and Thy1-APP transgenic mice. Remarkably, Aß levels 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 combinational approach to not only enhance synoptoplasticity but to alsomodify underlying Alzheimer’s disease pathology.