Sex differences in the expression of synaptic proteins in the brain of the TgCRND8 mouse model of Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is progressive, neurodegenerative disorder, characterized by memory loss and cognitive decline. Advanced age and female sex are the most prominent risk factors. Although epidemiological and clinical studies have provided evidence for sex differences, relevant molecular mechanisms are not well characterized. To determine if overexpression of AD-related genes had any effect on synaptic proteins from either side of the synapse, the pre-synaptic marker, synaptophysin, and the postsynaptic marker, PSD-95, were analyzed in the hippocampus and cortex of old CRND8 mice and their respective controls. We hypothesized that synaptic proteins that have been shown to be reduced in post-mortem brain samples in AD and in animal AD models, would show a more pronounced pattern of changes in females than in males. Hippocampal and cortical samples of 14-mo TgCRND8 and control mice (male and female) were analyzed on the gradient gel for the presence of amyloid beta. Western blot experiments were used to determine protein levels of synaptophysin and PSD95 in these same brain regions. Mortality rates were higher in female TgCRND8 than in males compared to their controls. The presence of amyloid beta was confirmed in cortex and hippocampus of all TgCRND8 mice. Western blot results revealed significant decreases in synaptophysin and PSD95 in the hippocampus of TgCRND8 females compared to controls (*p<0.05) but not in males. In the cortex, synaptophysin and PSD95 were decreased only in male TgCRND8 mice, while PSD95 showed a trend in decrease in female TgCRND8 mice. Our results confirm reports of decreased synaptic proteins in AD mouse brain, but we further show that these changes are region- and sex-dependent.