Suppression of APP signaling into nucleus by estrogens mediated through the complex formation between the estrogen receptor and Fe65

Departments of Pathology and Cell Biology and Molecular Oncology, USF College of Medicine and Programs of Molecular Oncology and Drug Discovery, H. Lee Moffitt Cancer Center, Tampa, Florida 33612-4799; Department of Medical Microbiology and Johnnie B. Byrd, Sr. Alzheimer's Center & Research Institute, USF College of Medicine, Tampa, Florida 33612-4799

	Abstract

The C-terminal fragment of the -amyloid precursor protein produced after cleavage by -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 17-estradiol inhibits the transcriptional and apoptotic activity of the APPct complex by a process involving the interaction of estrogen receptor (ER) with Fe65. ER-Fe65 complexes were detected both in vitro and in the mouse brain and recruitment of ER 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.