Suppression of β-Amyloid Precursor Protein Signaling into the Nucleus by Estrogens Mediated through Complex Formation between the Estrogen Receptor and Fe65

Estrogens are pleiotropic hormones that regulate the growth and differentiation of many diverse tissues. The actions of estrogens are mediated through estrogen receptors alpha and beta (ERα and ERβ, respectively), which belong to the steroid/thyroid nuclear receptor superfamily, a group of ligand-regulated, zinc finger-containing transcription factors (11, 45). The two ERs share a similar structural organization composed of an amino-terminal A/B region containing activation function 1 (AF-1), a central DNA binding domain (DBD), and a carboxyl-terminal ligand-binding domain (LBD) containing activation function 2 (AF-2). While AF-1 of the ER is constitutively active, the activity of AF-2 is strictly ligand dependent. In response to ligand activation, the ER forms a homodimer that binds estrogen response elements (EREs) and recruits multiple transcriptional coactivator complexes (23), leading to transcriptional stimulation. Besides their well-established role in the female reproductive system, estrogens also play an important role in regulating the neuronal activities of the pituitary gland, the hypothalamus, and other specific brain regions. It is generally believed that estrogens are neuroprotective and that the decrease in their abundance after menopause contributes to the development of neurodegenerative diseases such as Alzheimer's disease (AD). Multiple animal experiments and molecular analyses overwhelmingly support a neuroprotective role for estrogens (14, 31, 46). For example, estrogens have been shown to protect neurons from ischemic stroke, an activity that depends on ERα (9). 17β-Estradiol was shown to exert neurotrophic effects in tissue explants derived from the developing mouse hypothalamus and preoptic area (44). Synaptogenic effects of 17β-estradiol were demonstrated to occur in adult brain regions, such as the hippocampus, that are important for cognitive function (17, 51). For various models of neuronal damage, such as that caused by ischemic stroke, estrogens were reported to enhance neuronal survival (31, 46, 50). The β-amyloid precursor protein (APP) plays important roles in AD pathogenesis. It is a membrane-spanning protein with classical features of an orphan G protein-coupled receptor that is physiologically processed by cleavages with α- or β- and γ-secretase. After cleavage by β-secretase, APP is further cleaved in the transmembrane region by γ-secretase. The resulting extracellular amyloid β-peptide (Aβ) is deposited in the senile plaques in the brains of AD patients, which are considered the hallmark of AD. Besides its role in neurodegeneration, APP has multiple cellular functions, which include cell adhesion and motility (37), synaptic transmission and plasticity (38), and memory (7). It is also important that APP is ubiquitously expressed and not restricted to the brain. Increased expression of APP protein has been described for oral squamous cell carcinoma (24), suggesting additional biological functions for APP in nonneuronal and cancer cells. Perhaps one of the most interesting findings about APP in recent times is the demonstration of its potential role in transcriptional regulation (4). Besides Aβ, γ-cleavage of APP releases its intracellular C-terminal fragment, or APPct, which moves to the nucleus with Fe65 (20, 22). Fe65 binds Tip60 (34), a histone acetyltransferase that is involved in regulating higher-order chromosome structure and consequential gene expression (21). In the present study, we demonstrate that estrogens inhibit the transcriptional activity of and apoptosis induced by the APPct transcriptional complex. Mechanistic investigations reveal that the transcriptional repression is due to the “tethering” of ERα to the APPct complex through Fe65. The potential functional significance of this inhibition and its relevance to the well-documented neuroprotective activities of estrogens and to their suspected role in preventing AD are discussed.