Figure 10.

Estrogen neuroprotection may involve two complementary pathways. Under basal conditions (solid lines), E2 increases expression of antiapoptotic Bcl-w and decreases expression of proapoptotic Bim, events that counteract the mitochondrial pathway of apoptosis. This may represent an estrogen maintenance pathway of neuron survival. Under toxic challenges such as Aβ exposure (dashed lines), E2 can inhibit activation of JNK, functionally mimicking the pharmacological JNK inhibitor SP600125. JNK activation induces the mitochondrial pathway of apoptosis involving decreased expression of Bcl-w and increased expression of Bim, followed by mitochondrial release of cytochrome c and Smac, and eventually neuron death. Because E2 does not alter basal JNK activity, such a protective mechanism may represent an estrogen response pathway that is activated after injury.