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

Abstract

IntroductionShort-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.MethodsTo 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.ResultsOur 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.ConclusionsTaken 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.

Human neural stem cell transplantation into the corpus callosum of Alzheimer's mice

“…This is in line with many reports of stem cell migration via white matter tracts 12, 13, 14. Given that stem cell efficacy is improved when coupled with trophic factor delivery,2, 16, 17, 18 facilitating increased NSC migration could provide enhanced and widespread neurotrophic support to local brain areas. Moreover, targeting the CC provides the largest migratory area for transplanted stem cells, likely more than any other intracranial target, enabling further enrichment throughout the diseased brain environment.…”

Part I: Minicircle vector technology limits DNA size restrictions on ex vivo gene delivery using nanoparticle vectors: Overcoming a translational barrier in neural stem cell therapy

“…Several preclinical models of CNS pathology have demonstrated the utility of genetically engineered NSCs for improving functional neurological outcomes [12][13][14][15][16]. Recent data prove that transplantation of NSCs engineered to release insulin-like growth factor (IGF-1) reduced plaque pathology and enhanced learning, cognitive and memory processes in a mouse model…”

Clinical Neurophysiological and Automated EEG-Based Diagnosis of the Alzheimer's Disease

“…Blurton-Jones et al [96] found that neural stem cell transplantation enhanced synaptic connectivity and improved cognition in AD patients. Stem cells of AD patients are genetically modified and implanted in their brain hallmarks.…”