Early Diagnosis Of Alzheimer's Disease And Experimental Study Of Human Neural Stem Cell Transplantation

Section I:The early diagnosis of Alzheimer's disease using PET imaging in APP/PS1 transgenic miceBackground and objective:Alzheimer's disease(AD)is leading cause of dementia with 460 billion suffers worldwide currently,causing heavy burden to the individuals,family and society.The early diagnosis and early treatment of AD may bring with a better outcome.Recent studies showed that brain metablolic changes often occur earlier than structural changes in AD,thus the assessment of metablolic changes can lead to an earlier diagnosis of AD.However,the serial assessment of early metabolic changes within AD brains is rarely reported.This study will use PET imaging to explore early brain glucose metabolic changes related with AD stages,with a purpose of providing evidence for early diagnosis of AD.Methods:In this study,we used Morris water maze(WWM)to assess age-related behavioral changes of APP/PS1 transgenic mice of AD(2,3.5,5 and 8 month-old mice mimics the pre-,sub-,early-and sub-stage of AD,respectively).Thereafter,we examined the AD mice of different ages using FDG-PET imaging in order to explore age-and brain region-specific(hippocampus,entorhinal cortex,frontal cortex,striatum,thalamus,and corpus callosum)changes of glucose metabolism(expressed as the relative standardized utility value:SUVR),with a purpose of testing the possibility of detecting AD using regional glucose metabolism.Simultaneously,we explored the correlational relationship between hippocampal SUVR and MWM parameters after cognitive deficits.Results:In MWM,APP/PS1 mice aged 2 months shared similar behavioral and pathological performance with controls(prodromal-AD).By contrast,APP/PS1 mice passed all but training tests at 3.5 months but failed all MWM tests at 5 and 8 months,suggestive of partial or complete cognitive deficits(symptomatic-AD).We showed glucose utilization increase in multiple brain regions of APP/PS1 mice at 2 and 3.5 months but not at 5 and 8 months.Comparisons of SUVRs within brains showed higher glucose utilization in entorhinal cortex,hippocampus,and frontal cortex of AD mice at 2 and 3.5 months but in thalamus and striatum at 3.5,5 and 8 months than age-matched controls.By comparing SUVRs in entorhinal cortex and hippocampus,AD mice could be significnatly distinguished from age-matched controls at 2 and 3.5 months.Correlation analyses showed that hippocampal SUVRs were significantly correlated with MWM parameters in the AD mice in the symptomatic stage.Conclusion:These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with entorhinal cortex,hippocampus and frontal cortex first affected and that regional higher glucose utilization can be an early diagnostic marker for AD.Furthermore,hippocampal glucose metabolic changes can indicate the progression of Alzheimer's cognition after cognitive decline,at least in animals.Section II:Human neural stem cell transplantation rescues cognitive defects in APP/PS1 model of Alzheimer's diseaseBackground and objective:Alzheimer's disease(AD),the most frequent type of dementia,is featured by cognitive decline.A(3 depositions and neural degeneration within wide brain regions.To date,there is no cure for this disease.Neural stem cell(NSC)transplantation provides new promise for treating AD.Many studies report that intra-hippocampal transplantation of murine NSCs improved cognition in rodents with AD by alleviating neurodegeneration via neuronal complement or replacement.However,few reports examined the potential of human NSC(hNSC)transplantation for AD.This study is designed to explore the therapeutic role of transplanted hNSCs in AD mice with an aim to generate evidence for clinical application of NSC transplantation in AD patients.Methods:In this study,we implanted human brain-derived NSCs into bilateral hippocampus of APP/PS1 transgenic mice of AD to test the effects of hNSC transplantation on Alzheimer's behavior and neuropathology.At the same time,we assessed the survival,proliferation,migration and differentiation of hNSCs and evaluated the counts,structure,and connection of neural cells as well as the ultrastructural changes.Moreover,we determined the metabolic changes of AD mice brains after transplantation by using the magnetic resonance spectroscopy(MRS)technique.Results:Six weeks after transplantation of hNSCs,AD mice showed notable restoration in the recognition,learning and memory deficits but not anxiety tasks.Transplanted hNSCs engrafted into the brains of AD mice,proliferated,migrated dispersedly in broad brain regions,and some of them differentiated into neural cell types of central nervous system.Although A? plaques were not significantly reduced,the neuronal,synaptic and nerve fiber density was significantly increased in the hippocampus and frontal cortex of hNSCs-treated AD mice,suggesting of improved neuronal connectivity in AD brains after hNSC transplantation.Ultrastructural analyses confirmed the relatively well-maintained structures of synapses and nerve fibers in these mice.Furthermore,in-vivo magnetic resonance spectroscopy showed that hNSC-treated mice had notably increased levels of NAA and Glu in the hippocampus and frontal cortex,suggesting that neuronal metabolic activity was improved in AD brains after hNSC transplantation.Conclusion:These data suggest that hNSC transplantation rescued Alzheimer's recognition,learning and memory deficits but not anxiety of APP/PS1 transgenic mice of AD,transplanted hNSCs could survive,prolife,migrate and differentiate in AD mice brains,and that hNSCs enhanced neuronal connectivity and metabolic activity through a compensation mechanism in AD mice.This study provides preclinical evidence that hNSC transplantation can be a possible and feasible strategy for treating patients with AD.