Apoe Genotype And Gender Dependent Effects On Synaptic Mitochondrial Proteome And Its Implication In Sporadic Alzheimer’s Disease

The human apolipoprotein E (ApoE)-ε4allele and female gender are two well known risk factors in the development of Alzheimer’s disease (AD). However, the underlying mechanism has been a debate for a long time. It is well recognized that synaptic mitochondria play a crucial role in cognitive functions. In this study, by isolating synaptosomes and using label-free quantitative proteomics we reported, for the first time, the significantly decreased expression in synaptosomal proteome related to glucose, fatty acid, amino acid and oxidative phosphorylation pathways in the cortex of female ApoE4mice and that synaptic mitochondria were more susceptible to damage than non-synaptic mitochondria induced by both female gender and ApoE4factors. We further determined the glutathione/glutathione disulfide ratio and malondialdehyde level, which showed increased oxidative stress in the ApoE4and female mice. Our results revealed that ApoE4and female gender dependent dysfunction of synaptic mitochondrial proteins may be one of the molecular bases of the impaired cognitive function in AD.