IFN‐γ‐induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes

Abstract

b-Site APP cleaving enzyme 1 (BACE1) is an essential enzyme for the production of b amyloid. Since we found that injection of interferon-g (IFN-g) into young mouse brains increased BACE1 expression in astrocytes, we investigated molecular mechanisms underlying this process by cloning a putative BACE1 promoter. BACE1 promoter activity was differentially regulated by IFN-g in a region specific manner and down-regulated by an inhibitor of Janus kinase 2 (JAK2). A dominant negative mutant of signal transducer and activator of transcription 1 (STAT1) expression suppressed BACE1 promoter activity, and this was rescued by transfecting wild type STAT1. Electrophoretic mobility shift assay and promoter activity assays indicated that STAT1 binds directly to the putative STAT1 binding sequence of BACE1 promoter. Because IFN-g treatment induced STAT1 phosphorylation, we examined whether the expression of a suppressor of cytokine signaling (SOCS), negative regulator of JAK2, suppresses BACE1 promoter activity. The results show that SOCS1 or SOCS3 expression suppressed BACE1 promoter by blocking phosphorylation of Tyr701 residue in STAT1. Also, because IFN-g treatment specifically potentiated extracellular signal regulated MAP kinase (ERK) 1/2 activation, pretreatment of mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, PD98059, significantly attenuated IFN-g-induced BACE1 promoter activity and protein expression through blocking phosphorylation of Ser727 residue in STAT1, suggesting that ERK1/2 is associated with IFN-g-induced STAT1 signaling cascade. Taken together, our results suggest that IFN-g activates JAK2 and ERK1/2 and then phosphorylated STAT1 binds to the putative STAT1 binding sequences in BACE1 promoter region to modulate BACE1 protein expression in astrocytes. V V C 2006 Wiley-Liss, Inc.

Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

“…All procedures were performed in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and approved by the Local Animal Care Committee of Universitat de Barcelona (99/01) and Generalitat de Catalunya (99/ 1094). IFN-g-induced neuroinflammation was carried out as described with some modifications (28)(29)(30). Ten-week-old mice were subjected to injection of IFN-g (20 ng in 10 ml PBS) in the ventricular region (third ventricle) of the brain at the following coordinates relative to bregma: anterior-posterior, 20.3 mm; lambda, 0.0 mm; and 3.0 mm below the dural surface with the incisor bar at 3 mm above the interaural line.…”

The Role of Amyloid Precursor Protein Processing by BACE1, the β-Secretase, in Alzheimer Disease Pathophysiology

“…As a strong inflammatory reaction is present in AD brain, even a slight increase in glial BACE1 expression might substantially impact cerebral A␤ generation and exacerbate AD pathology. Certain pro-inflammatory molecules can elevate astrocytic Bace1 expression (38), and Bace1 levels appear to rise at sites of glial activation prior to plaque development (39). Interestingly, long-term nonsteroidal anti-inflammatory drug use reduces AD risk, an effect that may be mediated in part by activation of peroxisome proliferator-activated receptor-␥ and subsequent repression of BACE1 promoter activity (40).…”

Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling

“…Genomic DNA purified from HEK293 cells was used as a template to clone the BACE1 promoter region as described in Cho et al (2007). Three constructs were used: uBACE-1Ka, -1 bp to -994 bp; uBACE-1Kb, -930 bp to -1876 bp; and uBACE-2K, +50 bp to -2100 bp.…”

“…Oxidative molecules and nonsteroidal anti-inflammatory drugs are known to regulate BACE1 expression in in vitro model systems (Tamagno et al ., 2002;Sastre et al ., 2006). Interferon-gamma, a proinflammatory cytokine, induces BACE1 expression (Hong et al ., 2003;Cho et al ., 2007), and changes in BACE1 protein levels are associated with insulin-like growth factor 1 signaling, which is one of the major regulators of age-dependent events (Costantini et al ., 2006).…”