Abstract
Sex differences in the brain of mammals range from neuroarchitecture through cognition to cellular metabolism. The hippocampus, a structure mostly associated with learning and memory, presents high vulnerability to neurodegeneration and aging. Therefore, we explored basal sex-related differences in the proteome of organotypic hippocampal slice culture, a major in vitro model for studying the cellular and molecular mechanisms related to neurodegenerative disorders. Results suggest a greater prevalence of astrocytic metabolism in females and significant neuronal metabolism in males. The preference for glucose use in glycolysis, pentose phosphate pathway and glycogen metabolism in females and high abundance of mitochondrial respiration subunits in males support this idea. An overall upregulation of lipid metabolism was observed in females. Upregulation of proteins responsible for neuronal glutamate and GABA synthesis, along with synaptic associated proteins, were observed in males. In general, the significant spectrum of pathways known to predominate in neurons or astrocytes, together with the well-known neuronal and glial markers observed, revealed sex-specific metabolic differences in the hippocampus. TEM qualitative analysis might indicate a greater presence of mitochondria at CA1 synapses in females. These findings are crucial to a better understanding of how sex chromosomes can influence the physiology of cultured hippocampal slices and allow us to gain insights into distinct responses of males and females on neurological diseases that present a sex-biased incidence.
Highlights
Sex differences in the brain of mammals range from neuroarchitecture through cognition to cellular metabolism
Organotypic slices have been increasingly used as a major in vitro model for studying the cellular and molecular mechanisms related to neurodegenerative disorders that present a sex-biased incidence, such as Alzheimer’s and Parkinson’s diseases[13]
In order to identify possible specific proteins or metabolic pathways in the normal function of the hippocampus that may differ in females and males, an in-depth proteome quantitative comparison was carried out, along with transmission electron microscopy imaging and flow cytometry analysis
Summary
Sex differences in the brain of mammals range from neuroarchitecture through cognition to cellular metabolism. In the left hippocampus from bipolar I disorder patients, decreased concentrations of N-acetylaspartate + N-acetyl-aspartyl-glutamate (markers of neuronal integrity) and creatine + phosphocreatine (marker of energy buffer capacity) were associated with microglial activation and mood symptoms[9] Multiple metabolic pathways, such as glycolysis, TCA cycle, oxidative phosphorylation and phosphocreatine system were impaired in the hippocampus of APP/PS1 transgenic mice with Alzheimer’s disease. Organotypic slices have been increasingly used as a major in vitro model for studying the cellular and molecular mechanisms related to neurodegenerative disorders that present a sex-biased incidence, such as Alzheimer’s and Parkinson’s diseases[13] For this reason, it is critical to investigate the impact of sex chromosomes on the normal physiology of cultured slices, so that we can better understand how and why males and females are affected differently by such diseases. It may allow the enhancement of accuracy and effectiveness in the clinical care of patients, personalizing healthcare, especially in those diseases with a sex component
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