A proteomic study indicating susceptibility to excitotoxicity induced by the N-methyl-D- aspartate receptor hyperfunction as a potential mechanism underlying differences in cognitive function between males and females in a Thai healthy population

Abstract

Abstract Intact cognitive function is dependent on the precise exchange of information between neurons. Sex differences in cognitive function exist, but they are not stable, undergoing dynamic change during the lifespan. However, our understanding of how sex-related neural information transmission evolves with age is still in its infancy. This study was designed to investigate the molecular mechanisms underlying age-related sex differences in cognitive function in a Thai healthy population, as well as to determine the sex-dependent protein complexes for predicting cognitive aging. The Wisconsin Card Sorting Test (WCST) was performed to assess cognitive function in 199 Thai healthy subjects (aged 20–70 years). The results showed that males outperformed females in two of the five WCST sub-scores: %Corrects and %Errors, with a higher percentage of total corrects and a lower total errors rate. Sex differences in these scores were related to aging, and it became noticeable in those over 60. Moreover, the label-free proteomics method and bioinformatic analysis were also used to investigate the age-related alternations in the expression profiles of sex-specific neurotransmission-related proteins. According to the findings, differently expressed individual proteins and protein complexes between Thai healthy men and women were related to the potential excitotoxicity induced by N-methyl-D-aspartate type glutamate receptor (NMDAR) hyperfunction, with females might be more susceptible to such neurotoxicity, as indicated by their cognitive performance. The NMDAR complex was enriched exclusively in elderly female samples, implying that later in life, higher than optimal levels of NMDARs function and loss of estrogen neuroprotective, resulted in a loss of brain environment homeostasis and impaired cognitive function in elderly female subjects. This could explain why the sex differences in %Corrects and %Errors were only significant in the elderly group, and NMDAR protein complex enrichment in serum could be suggested as a potential indication for predicting cognitive aging in Thai healthy females.