Medicine and Programs of Molecular Oncology and Drug Discovery, H. Lee Moffitt

2 The C-terminal fragment of the β-amyloid precursor protein produced after cleavage by γ-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 acetyl transferase Tip60. The present studies show that 17β-estradiol inhibits the transcriptional and apoptotic activity of the APPct complex by a process involving the interaction of estrogen receptor α (ERα) with Fe65. ERα-Fe65 complexes were detected both in vitro and in the mouse brain and recruitment of ERα 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