Estrogen activates protein kinase C in neurons: role in neuroprotection

It has been previously demonstrated that estrogen can protect neurons from a variety of insults, including beta-amyloid (Abeta). Recent studies have shown that estrogen can rapidly modulate intracellular signaling pathways involved in cell survival. In particular, estrogen activates protein kinase C (PKC) in a variety of cell types. This enzyme plays a key role in many cellular events, including regulation of apoptosis. In this study, we show that 17beta-estradiol (E-2) rapidly increases PKC activity in primary cultures of rat cerebrocortical neurons. A 1 h pre-treatment with E-2 or phorbol-12-myristate-13-acetate (PMA), a potent activator of PKC, protects neurons against Abeta toxicity. Protection afforded by both PMA and E-2 is blocked by pharmacological inhibitors of PKC. Further, depletion of PKC levels resulting from prolonged PMA exposure prevents subsequent E-2 or PMA protection. Our results indicate that E-2 activates PKC in neurons, and that PKC activation is an important step in estrogen protection against Abeta. These data provide new understanding into the mechanism(s) underlying estrogen neuroprotection, an action with therapeutic relevance to Alzheimer's disease and other age-related neurodegenerative disorders.