P3‐346: Intensive cognitive stimulation increases function in the temporal cortex and precuneus in mild cognitive impairment

Abstract

Background:Alzheimer’s disease (AD) is the leading cause of age-related dementia, yet currently approved therapies are largely palliative. There is therefore a critical need to identify and test novel approaches to treat this disorder. We previously showed that murine neural stem cell (mNSC) transplantation improves cognition and enhances synaptic connectivity in aged 3xTg-AD mice. As most transgenic AD models exhibit little neuronal loss, we also assessed mNSC transplantation in an inducible model of hippocampal ablation (CaM/ Tet-DT A mice). Despite extensive death of CA1 neurons, mNSCs increased synaptic density and improved cognition in this model. In order to translate this NSC approach into potential clinical investigation, we have initiated a study testing the efficacy of human central nervous system stem cells (hCNS-SCns) in both the above transgenic models. This cell transplantation approach is currently being tested in other CNS indications and has an established human safety profile from two Phase I studies involving transplantation into the brain. Methods: Immunosuppressed 3xTg-AD and CaM/ Tet-DT A mice received hippocampal transplants of hCNS-SCns. One-month after transplantation, mice were tested on a battery of behavioral tasks followed by histological and biochemical analysis. Results: We have found that hippocampal transplantation of hCNSSCns improves cognition in both 3xTg-AD and Cam/Tet-DT A mouse models. Assessments in Morris water maze, context-dependent object recognition, and place recognition revealed significant improvements in hCNS-SCns versus vehicle-injected mice. Evidence of increased presynaptic terminals in hCNS-SCns-injected mice was also noted. Conclusions: Taken together, our data reveal that hCNS-SCns can improve cognition and enhance synaptic connectivity in two complimentary models of neurodegeneration. Our studies suggest that human neural stem cell transplantation holds considerable therapeutic promise for AD.