17β-Estradiol and Progesterone Regulate Expression of β-Amyloid Clearance Factors in Primary Neuron Cultures and Female Rat Brain

Abstract

The accumulation of β-amyloid protein (Aβ) is a key risk factor in the development of Alzheimer's disease. The ovarian sex steroid hormones 17β-estradiol (E(2)) and progesterone (P(4)) have been shown to regulate Aβ accumulation, although the underlying mechanism(s) remain to be fully elucidated. In this study, we investigate the effects of E(2) and P(4) treatment on the expression levels of Aβ clearance factors including insulin-degrading enzyme, neprilysin, endothelin-converting enzyme 1 and 2, angiotensin-converting enzyme, and transthyretin, both in primary neuron cultures and female rat brains. Our results show that E(2) and P(4) affect the expression levels of several Aβ clearance factors in dose- and time-dependent manners. Most notably, expression of insulin-degrading enzyme is significantly increased by both hormones in cultured neurons and in vivo and is inversely associated with the soluble Aβ levels in vivo. These findings further define sex steroid hormone actions involved in regulation of Aβ, a relationship potentially important to therapeutic approaches aimed at reducing risk of Alzheimer's disease.

Estrogen: A master regulator of bioenergetic systems in the brain and body

“…This was paralleled by increased expression of genes involved in Aβgeneration. In addition to its role in promoting insulin/IGF-1 function, estrogen further promotes Aβdegradation and clearance by upregulating insulin-degrading enzyme (IDE) and neprilysin gene and protein expression (Jayaraman et al, 2012; Zhao et al, 2011b). …”

Iron increases APP translation and amyloid-beta production in the retina

“…The level of C83 is much higher than that of C99, which is expected since non-amyloidogenic cleavage by α-secretase is the predominant pathway for APP processing (Postina, 2008). We tested the effect of FAC on Aβ levels using a validated colorimetric ELISA (Dasari et al, 2010; Jayaraman et al, 2012; Thakker et al, 2009), which showed an increase in Aβ42, with no detectable change in Aβ40 (Fig. 3D).…”

Sex Hormones and Alzheimer’s Disease

“…The direct progesterone protecting actions against AD development and/or progression include regulation of β-amyloid metabolism by reducing Aβ production and decreasing the pool of soluble Aβ by enhancement of the non-amyloidogenic α-secretase pathway, decreasing Aβ accumulation through modulation of γ-secretases activities and increasing Aβ clearance by enhancing insulin-degrading enzyme expression and downregulation of β-secretase gene expression [85,86]. At the same time, progesterone reduces tau hyperphosphorylation and the serum level of endogenous progesterone is inversely correlated with tau accumulation, and at the same time, progesterone administration in transgenic AD mice improved cognitive performance in object recognition and T-maze task [87].…”