Increase of Zinc Finger Protein 179 in Response to CCAAT/Enhancer Binding Protein Delta Conferring an Antiapoptotic Effect in Astrocytes of Alzheimer’s Disease

Abstract

Reactive astrogliosis is a cellular manifestation of neuroinflammation and occurs in response to all forms and severities of the central nervous system (CNS)’s injury and disease. Both astroglial proliferation and antiapoptotic processes are aspects of astrogliosis. However, the underlying mechanism of this response remains poorly understood. In addition, little is known about why activated astrocytes are more resistant to stress and inflammation. CCAAT/enhancer binding protein delta (CEBPD) is a transcription factor found in activated astrocytes that surround β-amyloid plaques. In this study, we found that astrocytes activation was attenuated in the cortex and hippocampus of APPswe/PS1 E9 (AppTg)/Cebpd−/−mice. Furthermore, an increase in apoptotic astrocytes was observed in AppTg/Cebpd−/−mice, suggesting that CEBPD plays a functional role in enhancing the antiapoptotic ability of astrocytes. We found that Zinc Finger Protein 179 (ZNF179) was a CEBPD-regulated gene that played an antiapoptotic, but not proliferative, role in astrocytes. The transcriptions of the proapoptotic genes, insulin-like growth factor binding protein 3 (IGFBP3) and BCL2-interacting killer (BIK), were suppressed by ZNF179 via its interaction with the promyelocytic leukemia zinc finger (PLZF) protein in astrocytes. This study provides the first evidence that ZNF179, PLZF, IGFBP3, and BIK contributed to the novel CEBPD-induced antiapoptotic feature of astrocytes.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-014-8714-9) contains supplementary material, which is available to authorized users.

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

“…Furthermore, CEBPD have been suggested to contribute to apoptosis. It has been recently suggested to play dual roles in pro-and antitumor processes under certain conditions (39)(40)(41). Furthermore, upregulated caspase-3 and caspase-8 activity has been reported in response to CEBPD induction in prostate cancer (41), and CEBPD was involved in antiapoptosis in astroglioma U373MG cells by upregulating the antiapoptotic gene ZNF179 (40).…”

The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease

“…Thus, we assessed the effect of ASS234 on amyloid plaque burden in a fully characterized animal model of Al zheimer disease useful for preclinical studies. 27,35,36,38 The reca pitulation of amyloid pathology and cognitive deficits as seen in patients with Alzheimer disease and the relative quick onset of pathology and symptoms makes the APPswe/PS1ΔE9 transgenic mouse model suitable for investigating Alzheimer disease-related processes. Our results -that ASS234 treat ment alleviates scopolamineinduced disruption of acquisition memory and improves Alzheimer disease pathology in mice overexpressing APP -provide in vivo data that suggest ASS234 may limit Alzheimer disease progression.…”

“…Characteristically, the number of GFAPpositive cells pro gressively increases with age in the APPswe/PS1∆E9 trans genic mice. 36 As in the brains of patients with Alzheimer dis ease, neuroinflammation in the area of amyloid plaques was observed in mouse models of Alzheimer disease, including the APPswe/PS1∆E9 transgenic mice, as shown by astrocytic and microglial reactivity (gliosis) 35,36,38 and association be tween neuroinflammation markers and soluble or insoluble Aβ or fibrillar amyloid plaque loads. 56 To identify the effect of ASS234 treatment on neuroinflammation, we thus exam ined whether anomalous astrocytic and microglial activation in transgenic mice was reversed by ASS234 treatment.…”

“…As microgliosis and astrocytosis are prominent aspects of this Alzheimer disease mouse model indicative of neuro inflammation, [35][36][37][38] we identified the effect of ASS234 on neuroinflammation through the evaluation of the immuno histochemical distribution of the astrocyte marker protein GFAP (Fig. 5A, B and E) and of the microglia/macrophage specific protein Iba1 (Fig.…”

Astrocytic CCAAT/Enhancer-Binding Protein Delta Contributes to Glial Scar Formation and Impairs Functional Recovery After Spinal Cord Injury

“…This protein is expressed at relatively low levels under normal physiological conditions and is upregulated in a number of inflammatory diseases by a variety of extracellular stimuli, such as IL-6, IL-1β, and tumor necrosis factor (TNF)-α [22–24]. Activated C/EBPδ in astrocytes promotes chemo-attraction and migration of microglia/macrophages [24]; it also contributes to the resistance of cell death [24] and attenuates macrophage-mediated phagocytosis of damaged neurons [23], suggesting its involvement in neuro-inflammatory and anti-apoptotic responses.…”