Estrogen-induced cell signalling in a cellular model of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is characterised by deposition of a 4 kDa amyloid-β peptide (Aβ) into senile plaques of the affected brain. Aβ is a proteolytic product of the membrane protein, amyloid precursor protein (APP). An alternative cleavage pathway involves α-secretase activity and results in secretion of a 100 kDa non-amyloidogenic APP (sAPPα) and therefore a potential reduction in Aβ secretion. We have shown that estrogen induces α-cleavage and therefore results in the secretion of sAPPα. This secretion is signalled via MAP-kinase and PI-3 kinase signal-transduction pathways. These pathways also have the potential to inhibit the activation of glycogen synthase kinase 3β (GSK), a protein involved in cell death. Therefore, the aim of this work was to further elucidate the estrogen-mediated signaling pathways involved in APP processing, with particular emphasis on GSK activity. By stimulating rat hypothalamic neuronal GT1-7 cells with estradiol, we found that estrogen decreases the activation state of GSK via the MAP kinase pathway. Moreover, the inhibition of GSK activity by LiCl causes enhanced sAPPα secretion in a pattern similar to that seen in response to estrogen, suggesting a pivotal role for this deactivation in APP processing. Further, inactivation of GSK by estrogen can be confirmed in an in vivo model. Elucidation of the signaling pathways involved in APP processing may help to understand the pathology of AD and may also prove beneficial in developing therapeutic strategies to combat AD.