Sex-specific gonadal status determines prefrontal cortex proteome response to tibolone

Area of Science:

• Neuroscience
• Endocrinology
• Proteomics

Background:

• Gonadal hormones influence sex differences in brain function and neurodegenerative disease.
• Hormone therapy outcomes for neurodegenerative diseases vary based on treatment timing post-menopause.
• Tibolone, a synthetic steroid, shows neuroprotective potential, but its mechanisms in different hormonal states are unclear.

Purpose of the Study:

• To investigate the sex-specific and shared proteomic responses to gonadal hormone deprivation and Tibolone treatment in the prefrontal cortex (PFC).
• To test the hypothesis that Tibolone's efficacy on the PFC proteome is gonad-dependent in male and female mice.

Main Methods:

• Proteomic analysis of mouse prefrontal cortex.
• Dimensionality reduction techniques to analyze sex-specific and shared proteomic responses.
• Functional enrichment analysis to identify regulated pathways.

Main Results:

• Gonadectomy caused PFC proteome convergence in both sexes, reducing sex-specific differences in calcium regulation, cytoskeletal function, and mitochondrial metabolism.
• Tibolone induced distinct sex-specific proteomic changes in intact animals but converged toward shared pathways in gonadectomized animals.
• Differential regulation of synaptic plasticity, neurotransmitter signaling, and cellular stress response pathways was observed.

Conclusions:

• The neurosteroid environment significantly alters hormone therapy efficacy, supporting the critical window hypothesis.
• Optimal neuroprotection strategies necessitate sex-specific and timing-specific approaches.
• This study provides a molecular framework for precision hormone therapy in neurodegeneration.