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

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Abstract
Progesterone exerts a variety of actions in the brain, where it is rapidly metabolized to 5α‐dihydroprogesterone (DHP) and 3α,5α‐tetrahydroprogesterone (THP). The effect of progesterone and its metabolites on the expression and phosphorylation of the microtubule‐associated protein Tau and glycogen synthase kinase 3β (GSK3β), 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 GSK3β assessed in whole hypothalamic homogenates. In contrast, progesterone and its metabolites resulted in a significant decrease in the expression of Tau and GSK3β 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 GSK3β, but did not affect the phosphorylation of an epitope of Tau (Ser262) that is GSK3β insensitive. These effects were accompanied by a decrease in the phosphorylation of GSK3β 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 GSK3β. The regulation of Tau expression and phosphorylation by progesterone may contribute to the hormonal regulation of cerebellar function by the modification of neuronal cytoskeleton. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007