Trisha Tomcy (URCAD)

Investigating Estrogen-Dependent Neuroimmune Response Across Menopausal-like Stages in Astrocytic Culture

Women are disproportionately affected by neurodegenerative diseases. Changes in estrogen levels may contribute to this increased vulnerability. Estrogens are neuroprotective hormones that regulate immune signaling in the brain by suppressing pro-inflammatory gene transcription. Neurodegenerative risk rises after menopause, when estrogen declines. Although hormone replacement therapy—which reintroduces estrogen after its decline—has been explored, its efficacy remains controversial and appears to depend on timing, but the mechanisms behind it remain unclear. Neuroinflammation, an early indicator of neurodegenerative disorders, becomes damaging when excessive. Astrocytes are central regulators of neuroimmune responses, releasing pro-inflammatory cytokines like TNF-α and IL-1β. Estrogen receptor-β signaling in astrocytes, not neurons, may support cognitive health.

This project investigated whether loss and reintroduction of estrogen during menopausal-like stages alters astrocytic inflammatory responses. We hypothesized that early estrogen re-exposure reduces pro-inflammatory activation, while delayed re-exposure results in dysregulated inflammatory signaling. Human neural stem cell–derived astrocytes received estrogen withdrawal followed by early or late re-exposure prior to TNF-α and IL-1β stimulation. Neuroinflammatory responses were quantified using confocal microscopy and immunofluorescent staining for NF-κB—a regulator of inflammatory gene expression—, and GFAP and C3—markers for reactive astrocytes. This work aims to provide insight into how age-related estrogen changes may shape vulnerability to neurological disease.