Inhibitory Interneuron Progenitor Transplantation Improves Cognitive Impairment In APP/PS1 Mice

Objective:This project aim to study whether inhibitory interneuron progenitor transplantation improve the cognitive deficiency of APP/PS1 mice.And it might provide a new theoretical basis for the clinical treatment of Alzheimer's disease and other neurodegenerative diseases.Methods:1.Various intemeuron subtypes including PV+,CR + and NPY + intemeurons in hippocampal DG,CA1 and CA3,and cortex were analyzed in APP/PS1 and WT mice at different developmental stages(2,7,and 12 months old)by immunofluorescence staining with corresponding antibodies.2.MGE-derived precursor cells of EGFP transgenic mouse E13.5 days,which were expressed green fluorescent protein,were isolated and transplanted into the hippocampus of APP/PS1 mice.Cell viability and migration distance were analyzed on 7th days,1 month and 2 months after transplantation.3.The number and proportion of GAD67+,PV+,CR + and NPY + intemeurons were analyzed by immunofluorescence to investigate the differentiation ability of these stem cells to interneurons two months after MGE-derived precursor cells transplantation4.Morris water maze and new object recognition were used to test whether the learning and memory ability of APP/PS1 mice was improved two months after MGE-derived precursor cells transplantation.5.A? plaques,neuroinflammation and synapses were analyzed in APP/PS1 mice by immunofluorescence staining two months after MGE-derived precursor cells transplantation.6.The hyperexcitability in APP/PS1 mice transplanted with or without stem cells were tested by EEG to study whether the hyperexcitability was restored in these transgenic mice.7.Clonazepam,which increases the effect of the neurotransmitter GABA,was injected to APP/PS1 mice,the hyperexcitability were analyzed by EEG.Results:1.The number of PV+,CR+,and NPY+ interneurons were progressively decreased in both WT and APP/PS1 mice hippocampus with age.And the loss of these interneurons in APP/PS1 mice was significantly severe compared to that in WT controls.2.Transplanted stem cells exhibit efficient migration after either 1 or 2 month after transplantation.3.Transplanted stem cells can differentiate into several interneuron subtypes successfully 2 months after transplantation.4.Transplanted stem cells can improve learning and memory of APP/PS1 mice.5.Transplanted stem cells had no effect on A?,neuroinflammation and synapse.6.Transplanted stem cells can improve the brain hyperexcitability of APP/PS1 mice.7.Clonazepam can improve the excitability of APP/PS1 mice brain.Conclusion:MGE-derived precursor cells transplantation to the hippocampus of APP/PS1 mice decreased the hyperexcitability,and thus improve their cognitive deficiency,but have no effect on A? plaques,neuroinflammatory and synapses.