The effect of aging on the subcellular distribution of estrogen receptor‐alpha in the cholinergic neurons of transgenic and wild‐type mice

Abstract

The degeneration of the basal forebrain cholinergic system plays an important role in cognitive deterioration in aging and Alzheimer's disease. Brain cholinergic neurons and their projections are affected by changes in the circulating levels of estrogens, which exert their effects mainly through the estrogen receptors. In this study, we investigated the effect of aging, estrogen status and transgenic genotype on the number of cholinergic neurons and the estrogen receptor alpha (ERalpha) content in the medial septum-vertical limb of the diagonal band of Broca. We used 6- and 12-month-old female double transgenic mice carrying mutated human amyloid precursor protein (APPswe) and presenilin-1 (PS1-A246E), and their nontransgenic littermate controls, which had been sham-operated or ovariectomized at the age of 3 months. Brain sections were double immunostained for choline acetyltransferase (ChAT) and ERalpha and used for stereological cell counting. We found that the number of ChAT-immunoreactive (ir) neurons containing nuclear ERalpha-ir was significantly lower in 12- than in 6-month-old mice. However, the age of the mice, the transgenic genotype or ovariectomy had no effect on the total number of ChAT-ir neurons, or on the number and percentage of all ChAT-ir neurons that contained ERalpha. These results indicate that aging is associated with translocation of ERalphas from the nucleus to the cytoplasm. We propose that this phenomenon is linked to those age-related processes known to be involved in inhibiting ERalpha binding to nuclei.

Estrogen Induces Estrogen Receptor α-Dependent cAMP Response Element-Binding Protein Phosphorylation via Mitogen Activated Protein Kinase Pathway in Basal Forebrain Cholinergic NeuronsIn Vivo

“…The origin of cell type differences in estrogen-induced CREB phosphorylation can be derived from the different expression of ERs between GnRH and cholinergic neurons. Although GnRH neurons predominantly express ER␤ (Herbison and Pape, 2001), cholinergic neurons mainly express ER␣ (Shughrue et al, 2000;Kalesnykas et al, 2005), and indeed we found that estrogeninduced increase in pCREB-IR in cholinergic neurons was completely blocked in ER␣KO mice. Furthermore, in the striatum, where no ER␣ is present in cholinergic neurons (Shughrue et al, 2000), E2 failed to increase CREB phosphorylation in these neurons.…”

“…Estrogen receptors (ERs) are present in cholinergic neurons, with mainly ER␣ found in BFC neurons (Shughrue et al, 2000;Kalesnykas et al, 2005). Generally, estrogen affects neurons two different ways: either via direct DNA-binding and transcriptional activity of liganded ERs (classical effect) or via rapid intracellular signaling pathways activation through protein kinase A (PKA) and mitogen activated protein kinase (MAPK) (Carlstrom et al, 2001;Kim et al, 2002;Guerra et al, 2004;Vasudevan et al, 2005;Zhao et al, 2005).…”

Age-related changes in the expression of ER-β mRNA in the female rat brain

“…These data indicate that decreases in maximal nuclear ER concentrations may be the result of a decreased number 6 of cytoplasmic ERs available for translocation and not to changes in the subcellular distribution of the receptor in aging rats . While previous studies showed that ER-α expression changes during aging in the boundaries of the medial septal-vertical limb of the diagonal band of Broca, periventricular preoptic nucleus, ventromedial nucleus and hippocampus in the female rat brain (Funabashi et al, 2000;Adams et al, 2002;Wilson et al, 2002;Chakraborty et al, 2003a;Kalesnykas et al, 2005;Mehra et al, 2005), little is known about the effect of aging on the level of ER-β expression.…”

Aging and substitutive hormonal therapy influence in regional and subcellular distribution of ERα in female rat brain

“…Because of the potential importance of this receptor in the mediating effects of changing estradiol levels with aging, many studies achieved the amount of global immunostaining and distribution of ERα in several brain areas, such as the hippocampus (Adams et al 2002;Mehra et al 2005) or hypothalamus (Funabashi et al 2000). Furthermore, it was reported that not only is there an age regulation of the intensity of immunostaining, but also an evident influence of aging in the subcellular distribution of this receptor (Ishunina et al 2000;Milner et al 2001;Kalesnykas et al 2005). In ovariectomized animals, the effect of the sexual hormones in the ERα level and its localization within the cell, as is described by many researchers has also been widely demonstrated (Adams et al 2002;Wilson et al 2002;Stirone et al 2003).…”