β-amyloid-induced gonadotropin-releasing hormone decline involving Forkhead transcription factor FOXO3a and nuclear factor-κB

Abstract

Previously, it has been demonstrated that aging is controlled by the hypothalamus, and that hypothalamus-driven programmatic aging is associated with nuclear factor-κB (NF-κB)-mediated gonadotropin-releasing hormone (GnRH) decrease. Abundant accumulation of β-amyloid (Aβ) has been observed in brains of cognitively normal elderly. However, it is unclear whether Aβ neurotoxicity is involved in aging-associated hypothalamic GnRH decline. GT1-7 cells, which are a cell line of hypothalamic GnRH neurons, were used in the current study to investigate whether and how Aβ decreased GnRH release. The results of the current study demonstrated that Aβ impaired the release of GnRH through activation of NF-κB. Mechanistic studies revealed that Aβ activated NF-κB via Forkhead box protein O3a, thereby inhibiting gnrh1 gene. The results of the present study provided novel insights into the mechanisms underlying aging-dependent hypothalamic GnRH decline.