Effects of progesterone and its reduced metabolites, dihydroprogesterone and tetrahydroprogesterone, on the expression and phosphorylation of glycogen synthase kinase‐3 and the microtubule‐associated protein Tau in the rat cerebellum

Abstract

Progesterone exerts a variety of actions in the brain, where it is rapidly metabolized to 5alpha-dihydroprogesterone (DHP) and 3alpha,5alpha-tetrahydroprogesterone (THP). The effect of progesterone and its metabolites on the expression and phosphorylation of the microtubule-associated protein Tau and glycogen synthase kinase 3beta (GSK3beta), a kinase involved in Tau phosphorylation, were assessed in two progesterone-sensitive brain areas: the hypothalamus and the cerebellum. Administration of progesterone, DHP, and THP to ovariectomized rats did not affect Tau and GSK3beta assessed in whole hypothalamic homogenates. In contrast, progesterone and its metabolites resulted in a significant decrease in the expression of Tau and GSK3beta in the cerebellum. Furthermore, progesterone administration resulted in an increase in the phosphorylation of two epitopes of Tau (Tau-1 and PHF-1) phosphorylated by GSK3beta, but did not affect the phosphorylation of an epitope of Tau (Ser262) that is GSK3beta insensitive. These effects were accompanied by a decrease in the phosphorylation of GSK3beta in serine, which is associated to an increase in its activity, suggesting that the effect of progesterone on Tau-1 and PHF-1 phosphorylation in the cerebellum is mediated by GSK3beta. The regulation of Tau expression and phosphorylation by progesterone may contribute to the hormonal regulation of cerebellar function by the modification of neuronal cytoskeleton.

Regulation of the phosphoinositide‐3 kinase and mitogen‐activated protein kinase signaling pathways by progesterone and its reduced metabolites in the rat brain

“…The PI3K signaling pathway is involved in the regulation of neuronal development, neuronal survival, synaptic plasticity, synaptic transmission, and cognition (Skeberdis et al, 2001;Arimura and Kaibuchi, 2005;van der Heide et al, 2006;Zhao et al, 2006;Vetiska et al, 2007), and PI3K appears to mediate neuroprotective effects of progesterone in organotypic cultures of the cerebral cortex (Kaur et al, 2007). In the cerebellum, progesterone regulates the activity of glycogen synthase kinase-3 (GSK3) and the phosphorylation of the microtubule-associated protein tau (Guerra-Araiza et al, 2007). These effects of progesterone, which could influence axonal transport and axonal growth and remodeling (Lindwall and Cole, 1984;Avila et al, 2004), may be mediated in part by the hormonal modulation of the PI3K/ Akt signaling pathway, insofar as Akt is upstream of GSK3, which, in turn, regulates the phosphorylation of tau (Guerra-Araiza et al, 2007).…”

“…In the cerebellum, progesterone regulates the activity of glycogen synthase kinase-3 (GSK3) and the phosphorylation of the microtubule-associated protein tau (Guerra-Araiza et al, 2007). These effects of progesterone, which could influence axonal transport and axonal growth and remodeling (Lindwall and Cole, 1984;Avila et al, 2004), may be mediated in part by the hormonal modulation of the PI3K/ Akt signaling pathway, insofar as Akt is upstream of GSK3, which, in turn, regulates the phosphorylation of tau (Guerra-Araiza et al, 2007). Progesterone is rapidly metabolized in the brain by the enzyme 5a-reductase into its reduced derivative DHP, which subsequently is further reduced to THP (also known as allopregnanolone) by the enzyme 3a-hydroxysteroid dehydrogenase (Garcia-Segura and Melcangi, 2006).…”

Progesterone and Estrogen Regulate Alzheimer-Like Neuropathology in Female 3xTg-AD Mice

“…Specifically, E2 has been reported to reduce GSK-3␤ activity (Goodenough et al, 2005), a kinase that phosphorylates tau sites associated with neuropathology (Ishizawa et al, 2003). Recent data suggest that acute P4 treatment can decrease expression of both tau and GSK-3␤ in rat cerebellum, but net increases in both GSK-3␤ activity and tau phosphorylation were also observed (Guerra-Araiza et al, 2007). It is unclear how continuous P4 affects GSK-3␤, although our data predict that extended P4 exposure alters the balance of taurelevant kinase and phosphatase activities to yield a net decrease in pathological tau phosphorylation.…”

Neuroactive steroids: State of the art and new perspectives

“…Interestingly, the effects of estradiol on the growth of neurites in vitro are paralleled by an increase in the expression of microtubule-associated proteins, such as Tau or microtubule-associated protein 2 [13,14]. In addition, estradiol and progesterone (PROG) regulate the expression of microtubule-associated protein 2 in the brain in vivo [15], and testosterone [16], estradiol [17,18] and PROG [19] regulate Tau phosphorylation, which is essential for its association with axonal microtubules and the regulation of axonal growth. Estradiol also regulates the interaction of Tau with neurotransmitter receptors [20].…”