Proteomic association with age-dependent sex differences in Wisconsin Card Sorting Test performance in healthy Thai subjects

Abstract

Sex differences in cognitive function exist, but they are not stable and undergo 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 utilized the Wisconsin Card Sorting Test (WCST) and the label-free proteomics method with bioinformatic analysis to investigate the molecular mechanisms underlying age-related sex differences in cognitive performance in 199 healthy Thai subjects (aged 20-70 years), as well as explore the sex-dependent protein complexes for predicting cognitive aging. The results showed that males outperformed females in two of the five WCST sub-scores: %Corrects and %Errors. Sex differences in these scores were related to aging, becoming noticeable in those over 60. At the molecular level, differently expressed individual proteins and protein complexes between both sexes are associated with the potential N-methyl-D-aspartate type glutamate receptor (NMDAR)-mediated excitotoxicity, with the NMDAR complex being enriched exclusively in elderly female samples. These findings provided a preliminary indication that healthy Thai females might be more susceptible to such neurotoxicity, as evidenced by their cognitive performance. NMDAR protein complex enrichment in serum could be proposed as a potential indication for predicting cognitive aging in healthy Thai females.

Figure 1

Sex differences in WCST sub-scores after controlling age and education level. Graphs were generated using flexplot package in R-programming ver. 4.1.2. Correct = %Corrects, Errors = %Errors, Fst Category = 1st Category, No..set PE = PE.

Figure 2

Change of sex differences in WCST scores %Corrects and %Errors with age. Graphs were generated using flexplot package in R-programming ver. 4.1.2. Correct = %Corrects, Errors = %Errors.

Figure 3

Protein intensities comparison of those 6 DEPs upregulated in males. ***FDR ≤ 0.01.

Figure 4

The top three processes in each GO class with DEPs significantly enriched.

Figure 5

Protein–protein interaction networks of 26 DEPs. The purple line indicates binding, the blue line indicates expression, the black line indicates chemical reactor, the solid gray indicates molecular transport, and the gray dotted line indicates regulation. The plus sign indicates positive regulation.

Figure 6

Expression levels of such 26 DEPs between males and females. The expression gradient is from green (minimum) to red (maximum).

Figure 7

Neurotransmission-related protein complexes are only enriched in males or females. Graph was generated on the website of COMPLEAT. Color gradient varies from red (max input score) to blue (min input score). Dashed lines indicate interactions.

Figure 8

Neurotransmission-related protein complexes are enriched only in elderly males or females. Graph was generated on the website of COMPLEAT. Color gradient varies from red (max input score) to blue (min input score). Dashed lines indicate interactions.