Acceleration of amyloidogenesis and memory impairment by estrogen deficiency through NF-κB dependent beta-secretase activation in presenilin 2 mutant mice

• Ovariectomy accelerates PS2 mutation driven Aβ deposition and memory dysfunction.
• Amyloidogenesis was promoted by ovariectomy in PS2 mutant mice.
• NF-ĸB activation was reduced by estrogen.
• Estrogen has a protect effect on PS2 mutation driven AD development through inhibiting NF-ĸB pathway.

Nearly 7–10 million people are living with Alzheimer’s disease (AD) worldwide. Senile plaques composed of β-amyloid (Aβ) are a pathological hallmark of Alzheimer’s disease. Presenilin 2 (PS2) mutations increase Aβ generation in the brains of AD patients. The Aβ is generated through the sequential cleavage of amyloid precursor protein by β- and γ-secretases. Additionally, increasing evidences suggest that estrogen can reduce the development of AD via regulation of β-secretases activity and beta-site APP-cleaving enzyme (BACE1) expression. But the underlying correlation mechanism of Aβ generation by PS2 mutations and estrogen remains to be clarified. To investigate the anti-amyloidogenesis effect of estrogen in a PS2 mutative condition, we examined memory impairment in ovariectomized PS2 mutation (N141I) mice in which cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, Western blot analysis, immunostaining, immunofluorescence staining, ELISA and enzyme activity assays were used to examine the degree of Aβ deposition in the brains. In the present study, Aβ accumulated more in the ovariectomized PS2 mutant mice brain, and greatly worsened memory impairment and glial activation as well as neurogenic inflammation. In parallel with increased memory impairment, activity of β-secretase and expression of the BACE1 increased in ovariectomized PS2 mutant mice. Much higher activity of NF-κB was observed by EMSA in ovariectomized PS2 mutant mice. In addition, the Aβ level was decreased by treatment of β-estradiol through inhibiting BACE1 expression in PS2 transfacted PC12 cells. These results suggest that mutation of PS2 can lead to NF-κB mediate amyloidogensis, and this effect can be amplified by the absence of estrogen.