Suppression of β-amyloid precursor protein signaling into the nucleus by estrogens mediated through complex formation between the estrogen receptor and Fe65

The C-terminal fragment of the beta-amyloid precursor protein produced after cleavage by gamma-secretase, namely, APPct or AICD, has been shown to form a multimeric complex with the adaptor protein Fe65 and to regulate transcription through the recruitment of the histone acetyltransferase Tip60. The present study shows that 17 beta-estradiol inhibits the transcriptional and apoptotic activities of the APPct complex by a process involving the interaction of estrogen receptor alpha (ER alpha) with Fe65. ER alpha-Fe65 complexes were detected both in vitro and in the mouse brain, and recruitment of ER alpha to the promoter of an APPct target gene (KAI1) was demonstrated. Our studies reveal a novel mechanism of estrogen action, which may explain the well-known neuroprotective functions of estrogens as well as the complex role of this female hormone in the pathogenesis of neuronal degeneration diseases.