ZNF787 and HDAC1 Mediate Blood-Brain Barrier Permeability in an In Vitro Model of Alzheimer's Disease Microenvironment.

The permeability of the blood-brain barrier (BBB) is increased in Alzheimer's disease (AD). This plays a key role in the instigation and maintenance of chronic inflammation during AD. Experiments using AD models showed that the increased permeability of the BBB was mainly caused by the decreased expression of tight junction-related proteins occludin and claudin-5. In this study, we found that ZNF787 and HDAC1 were upregulated in ß-amyloid (Aß)1-42-incubated endothelial cells, resulting in increased BBB permeability. Conversely, the silencing of ZNF787 and HDAC1 by RNAi led to reduced BBB permeability. The silencing of ZNF787 and HDAC1 enhanced the expression of occludin and claudin-5. Mechanistically, ZNF787 binds to promoter regions for occludin and claudin-5 and functions as a transcriptional regulator. Furthermore, we demonstrate that ZNF787 interacts with HDAC1, and this resulted in the downregulation of the expression of genes encoding tight junction-related proteins to increase in BBB permeability. Taken together, our study identifies critical roles for the interaction between ZNF787 and HDAC1 in regulating BBB permeability and the pathogenesis of AD.

Transcription factor ZNF22 regulates blood-tumor barrier permeability by interacting with HDAC3 protein.

Objective: The primary goals of this study were to investigate the potential roles of ZNF22 and HDAC3 as a histone deacetylase in regulating an increases in blood-tumor barrier (BTB) permeability and some of the possible molecular mechanisms associated with this effect. Methods: The expression of ZNF22 and HDAC3 in glioma-exposed endothelial cells (GECs) of BTB were detected transcription real-time PCR or western blot. The interaction of ZNF22 and HDAC3 in GECs associated with transcript effect was analyzed by means of Co-Immunoprecipitation and luciferase reporter assay. Results: In the present investigation, GECs expressed higher levels of ZNF22 as a zinc finger transcription factor and HDAC3 than endothelial cells. We then affirmed that silencing HDAC3 or ZNF22 led to a reduction in BTB permeability. By bioinformatics analysis, chromatin immunoprecipitation (ChIP) assays and luciferase assay, we found that ZNF22 had a target binding relationship with the promoter regions of ZO-1, Occludin, and Claudin-5 and negatively regulated the expression of ZO-1, Occludin, and Claudin-5. Furthermore, we revealed that HDAC3, as a co-transcript repressor with histone deacetylase activity, could interact with ZNF22 to hinder the expression of TJ-associated proteins, thereby further facilitating the permeability of BTB. Conclusion: ZNF22 acted as a transcription factor in conjunction with HDAC3 to modulate the expression of TJ-associated proteins, which was correlated with an increase in BTB permeability. These results may provide new strategies and targets for the chemotherapy of gliomas as well as intracranial infections.

TARBP2-stablized SNHG7 regulates blood-brain barrier permeability by acting as a competing endogenous RNA to miR-17-5p/NFATC3 in Aß-microenvironment.

Breakdown of blood-brain barrier (BBB) is recognized as serious pathological marker of Alzheimer's disease development. Studies confirmed that ß-amyloid (Aß) deposition induced high BBB permeability by disrupting tight junction (TJ) proteins formed from endothelial cells (ECs). Here, we found TARBP2, SNHG7 and NFATC3 in expressions were increased and miR-17-5p expression was decreased in Aß(1-42)-incubated ECs. Overexpression of TARBP2, SNHG7 and NFATC3 elevated BBB permeability and knockdown of them had converse results. Agomir-17-5p decreased BBB permeability and antagomir-17-5p increased BBB permeability. TARBP2 as a RNA-binding protein (RBP) bound to SNHG7 and resulted in longer half-life of SNHG7. The decreased expression of miR-17-5p had a negative post-transcriptional regulation to NFATC3, leading to the increased expression of NFATC3. In addition, SNHG7 regulated NFATC3 expression by acting as a molecule sponge targeting to miR-17-5p. NFATC3 inhibited TJ proteins expression by functioning as a transcription factor. TARBP2/SNHG7/miR-17-5p/NFATC3 pathway implied a potential mechanism in studies of BBB changes in AD pathological progression.