Serum proteomic analysis of neurotransmission-related proteins associated with cognitive functions in a Thai population

Abstract

Cognitive function refers to higher-order intellectual processes that gather and process information in the human brain. 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. Although previous research indicated that the changes in sex differences in normal neurological processes with age are modulated by complex molecules, with neurotransmission-related proteins being especially important. Our understanding of how sex-related neural information transmission evolves with age is still in its infancy. Therefore, this study was designed to investigate the molecular mechanisms underlying age-related sex difference in cognitive function in a Thai healthy population, as well as to determine the sex-dependent proteomic clocks 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 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, differentially expressed proteins between Thai healthy men and women were significantly enriched in the complement cascade, which may correspond to Glu-induced excitotoxicity. Another result of this research revealed that neurotransmission-related proteins were dynamically assembled as protein complexes in a sex-biased manner, relating to age. For example, the elevation of the cytosolic calcium ion concentration complex was only found in the females, and the N-methyl-D-aspartate type glutamate receptors (NMDARs) complex was enriched exclusively in elderly female samples. These results implied that females might be more susceptible to the excitotoxicity induced by NMDAR hyperfunction and this intensified with age, which was consistent with their performance on the WCST. The NMDAR level in serum would be a novel “proteomic clock” for predicting cognitive aging in Thai healthy women.

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