Apoe4Genotype Dependent Effect On Synaptic Mitochondrial Dysfunction And Oxidative Stress In Alzheimer’s Disease

ApoE4(Apolipoprotein E4) with an allele frequency of14%in these populations, is linked to an increased risk of developing sporadic AD as well as a decreased age of onset compared to inherited ApoE3.Oxidative stress in AD pathogenesis has played a key role, meanwhile, changes in synapse cannot be ignored. Recent studies suggest that ApoE, Synapse and oxidative stress are closely related. In this study, we aim to investigate how ApoE gene polymorphism effect oxidative stress and synapse in AD pathogenesis.We used the13months aged ApoE transgenic mice as the AD animal model. In behavior experiments, ApoE4/4mice showed a short-term (30mins interval) worse learning and memory abilities in novel object recognition test compared with ApoE3/3mice. In Y-maze test, the ApoE4/4mice did not represent cognitive impairment in both short and long-term test.Synaptosomes were isolated by the percoll gradient method for further using of label-free quantitative proteomics followed by Identification of purity with western blotting. The proteomics results showed significantly decreased expression in synaptosomal proteome related to glucosemetabolism,oxidative stress, and electron transfer chain pathways in the cortex of ApoE4mice.Malondialdehyde (MDA), which is formed by ROS degrading polyunsaturated lipids, was considered as a reliable marker of oxidative stress as well as the glutathione system. ApoE4/4transgenic mice displayed an increased MDA and GSSG level in the cortex. Furth more, decreased GSH/GSSG ratio was observed in ApoE4/4mice. In sum, there was an accumulation of oxidative stress in the cortex of ApoE4/4mice.In order to verify the results of proteomics, SOD2and COX IV, two key proteins related to oxidative stress and mitochondria electron transfer chain were measured by the Western Blotting. Consistent with the proteomics result, the expression of COXIV and SOD2protein level was significantly lower in the ApoE4/4transgenic mice.There was no change in the mRNA expression of genes involved in synaptic plasticity, oxidative stress and mitochondrial function followed by a significant different protein level in13month aged ApoE transgenic mice. In conclusion, our study suggested that the ApoE4genotype dependent synaptic mitochondrial dysfunction and increased oxidative stress in ApoE transgenic mice may contribute to the pathogenesis of AD.