Axonal Transportation In APP/PS1 Transgenic Mice And The Pathogenesis Of Alzheimer's Disease

Axoplasmic transportation plays an important role in neural information exchange and energy metabolism.The relative axoplasmic transport proteins,such as kinesin1 and transferrin receptor 1(TfR1),are involved in the process.Usually,TfR1 locates on postsynaptic membrane,which participates in axoplasmic transportation through its mediated endocytic regimen.Amyloid precursor protein(APP)can link with kinesin1 and participate in axoplasmic transportation as well.APP gene mutations can cause axonal transport disorders and often accompany with abnormal Tf R1 expression in the brain.Axonal transportation disorders may be the earliest appearance of Alzheimer's disease(AD)pathological changes,even earlier than the formation of senile plaques and nerve fibers.Unfortunately,few studies have reported on the roles of kinesin1 and TfR1 in AD pathogenesis.In this study,we used APP/PS1 transgenic mice and their primary cultures cells as AD animal and cell models to study the relationship between axonal transportation and AD pathogenesis,finally kinesin1 and TfR1's dysfunction were discussed during AD pathogenesis as well.Objective: To understand the relationship between axonal transport disorder and Alzheimer's disease,the expressions of axonal transportation,kinesin1,TfR1 and SIM-312 andthe transferrin receptor's 1 neuroprotection in Alzheimer's disease,in the hippocampus of APP/PS1 transgenic mice were investigated.Methods:The mice from postnatal day 30 to postnatal day 360 were used in the study with the immunofluorescent labeling and Western blot.In the meantime,Immunofluorescence and western blot were used to detect the expression of TfR1 in the APP/PS1 transgenic mice.he primary cultured hippocampal neurons were used as AD's cell model in the study.TfR1 expression and A?1-42 secretion were detected with Western blotting and Elisa assay respectively.On the other hand,the cultured neurons and their processes were labeled with TfR1 and MAP2 immunolabeling,and the TfR1-mediated axonal vesicles were observed with FM1-43 staining.Moreover,the RNA interference with TfR1 shRNA pGFP-V-RS was carried out as well.Results:(1)TfR1 expression in AD mice(APP/PS1 transgenic mice)decreased significantly after P 6M(postnatal 6 months),compared with WT mice.(2)Similarly,in cultured cells,after TfR1 gene silence,the neuronal processes became longer and thin,and the axonal vesicle transportation was blocked.(3)APP/PS1 transgenic mice had more A? plaques,more astrocytes,compared with the normal control group.However,the number of Kinesin1-positive cells increased in APP/PS1 transgenic mice after 9 months,and SIM-312 positive neurofilaments appeared tangled in the AD mice,after 6 months as well.Conclusion:(1)APP and PS1 gene mutation can lead to decreased expression of TfR1.(2)TfR1 sh RNA interference can increase the amount of A? secretion and impact neurite growth and axoplasmic vesiclr transportation.Therefore,we conclude that TfR1 may play an important role in neuroprotection.(3)Abnormal Kinesin1 and SIM-312 were involved in axonal transportation disorder in AD mice,suggesting they were the important pathogenic factors of AD.