Abstract
Alzheimer’s disease (AD) and prion diseases carry a significant inflammatory component. The astrocytic overexpression of CCAAT/enhancer-binding protein delta (C/EBPD) in prion- and AD-affected brain tissue prompted us to study the role of this transcription factor in murine model systems of these diseases. Ablation of C/EBPD had neither in the AD model (APP/PS1double transgenic mice) nor in the prion model (scrapie-infected C57BL/6 mice) an influence on overt clinical symptoms. Moreover, the absence of C/EBPD did not affect the extent of the disease-related gliosis. However, C/EBPD-deficient APP/PS1 double transgenic mice displayed significantly increased amyloid beta (Abeta) plaque burdens while amyloid precursor protein (APP) expression and expression of genes involved in beta amyloid transport and turnover remained unchanged. Gene expression analysis in mixed glia cultures demonstrated a strong dependency of complement component C3 on the presence of C/EBPD. Accordingly, C3 mRNA levels were significantly lower in brain tissue of C/EBPD-deficient mice. Vice versa, C3 expression in U-373 MG cells increased upon transfection with a C/EBPD expression vector. Taken together, our data indicate that a C/EBPD-deficiency leads to increased Abeta plaque burden in AD model mice. Furthermore, as shown in vivo and in vitro, C/EBPD is an important driver of the expression of acute phase response genes like C3 in the amyloid-affected CNS.
Highlights
CCAAT/enhancer-binding protein delta (C/EBPD) is a member of the CCAAT/enhancerbinding protein (C/EBP) family of transcription factors, which carry a conserved basic-leucine zipper domain directing dimerization and DNA binding
In the periphery the transcription factor C/EBPD acts as part of a regulatory circuit to drive and amplify innate immune responses triggered by bacterial infections [2, 31, 32]
We characterized here mice deficient for C/EBPD to learn more about a possible role of this transcription factor in Alzheimer’s disease (AD) and in prion diseases
Summary
CCAAT/enhancer-binding protein delta (C/EBPD) is a member of the CCAAT/enhancerbinding protein (C/EBP) family of transcription factors, which carry a conserved basic-leucine zipper domain directing dimerization and DNA binding. It is involved in the regulation of a diverse range of biological processes like inflammation and cellular differentiation. Basal C/ EBPD expression levels are typically low but are highly inducible by multiple stimuli [1]. In the periphery its role in the regulation of acute phase genes like complement component C3 and antichymotrypsin and, more generally, in innate immunity has been extensively studied. PLOS ONE | DOI:10.1371/journal.pone.0134228 July 31, 2015
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