Effect of age and sex differences on the abundances of neuronal, glial, and endothelial cells in non-diseased brain tissue

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Neuroinflammatory and neurodegenerative diseases are influenced by the complex interplay of different cell types within the brain, and understanding the proportions and dynamics of neuronal, glial, and endothelial cells is crucial for deciphering the mechanisms of these diseases. Certain risk factors, such as age and sex differences, are thought to play a significant role in the susceptibility, progression, and response to neurological disease. Therefore, investigation of age- and sex-related differences in cell type proportions is needed to elucidate the biological basis of these diseases. Advances in sequencing technology have enabled large-scale transcriptomic studies, such as the Genotype-Tissue Expression (GTEx) project, providing valuable resources for investigating the cellular landscape of the human brain. In this analysis, we used brain sample data from the GTEx project, comprising 1646 samples with an age range of 20-70 years. The relative abundance of excitatory and inhibitory neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells was estimated from the RNA sequencing data using a deconvolution-based analysis. Spearman correlation analysis between the individuals' calendar ages and cell type proportions revealed a statistically significant decrease in the proportion of neurons with increasing age. In contrast, the proportions of astrocytes and endothelial cells showed a significant increase. Furthermore, endothelial cells exhibited the strongest correlation coefficient, positively associating with age. In addition, the findings indicate sex-based differences in age-related changes to cell type proportions. An age-associated decrease in neuronal proportions was only observed in male donors, while no significant change was found in females. Additionally, an age-associated increase in astrocyte proportions was exclusively seen in males, whereas only females exhibited a significant increase in microglia proportions. Furthermore, we identified sex-based differences in baseline cell type proportions. Male originating samples exhibited higher proportions of excitatory neurons, while female samples showed higher proportions of microglia and endothelial cells. Our results show that both age and sex affect the proportions of cell types in non-diseased brain tissue samples. These findings contribute to our understanding of the effects of age and sex differences on the cellular composition of the brain and shed light on the potential roles of age and sex in neurological diseases.

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