Estrogen deficiency exacerbates Aβ-induced memory impairment through enhancement of neuroinflammation, amyloidogenesis and NF-ĸB activation in ovariectomized mice

Abstract

Estrogen is well known to have a preventative effect in Alzheimer's disease (AD) pathology. Several studies have demonstrated that nuclear factor kappa-B (NF-ĸB) can contribute to the effects of estrogen on the development of AD. We investigated whether NF-ĸB affects amyloid-beta (Aβ)-induced memory impairment in an estrogen-lacking condition. In the present study, nine-week-old Institute cancer research (ICR) mice were ovariectomized to block estrogen stimulation. Ten weeks after the ovariectomization, mice were administered with Aβ (300 pmol) via intracerebroventricular (ICV) infusion for 2 weeks. Memory impairment, neuroinflammatory protein expression, and amyloidogenic pathways were then measured. Ovariectomized mice demonstrated severe memory impairment, Aβ accumulation, neprilysin downregulation, and activation of NF-ĸB signaling compared to sham-control mice. In vitro experiments demonstrated that β-estradiol (10 μM) inhibited Aβ (1 μM)-induced neuroinflammation in microglial BV-2 cells and prevented Aβ-induced cell death in primary cultured neuronal cells. As in in vivo experiments, NF-ĸB activation was significantly upregulated in in vitro experiments. Furthermore β-estradiol treatment inhibited NF-ĸB activation in both of microglial BV-2 cells and cultured neuronal cells. These findings suggest that estrogen may protect against memory impairment through the regulation of Aβ accumulation and neurogenic inflammation by inhibiting NF-κB activity.

Keywords: Alzheimer disease (AD); Amyloid-beta (Aβ); Estrogens; NF-κB; Neuroinflammation.