Glutaminyl cyclase inhibitor contributes to the regulation of HSP70, HSP90, actin, and ribosome on gene and protein levels in vitro

Abstract

Because of the crucial roles of upregulated glutaminyl cyclase (QC) in the initiation and development of Alzheimer's disease (AD), QC inhibitors are supposed as disease-modifying agents for the treatment of AD. And reported compounds encourage this hypothesis greatly based on the remarkable anti-AD effects in vivo. To illustrate the mechanism in detail, the actions of a selected QC inhibitor (23) were assessed firstly in a cell system here. It was demonstrated that QC activities and the generation of pyroglutamate-modified β-amyloids in PC12 cells were both inhibited obviously after the treatment of 23.A total of 13 and 15 genes were up-and downregulated significantly in treated cells by RNA-sequencing analysis. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, WB, and immunofluorescence analysis supported the effects of 23 on the transcriptome of PC12 cells consequently. The expressions of chaperones, heat shock proteins (HSP) 70, and 90, were upreglutated, while gene expression of actin and the level of encoded protein were reduced significantly in PC12 cells with the treatment.Furthermore, the regulations of ribosome were observed after the treatment. These results indicate the potency of 23 to improve the translation, expression and folding regulation of proteins and affect the multivalent cross-linking of cytoskeletal protein and other proteins subsequently in the cell system and might contribute to the understanding of the mechanism of QC inhibitor as potential anti-AD agents.

Upregulation of Glutaminyl Cyclase Contributes to ERS-Induced Apoptosis in PC12 Cells

“…The sequences of the primers are presented in Table 1 . The cycling condition was 95°C for 30 s, followed by 40 cycles at 95°C for 5 s, and 60°C for 30 s. The fold induction was calculated as described previously [ 25 ].…”

The Development of Small Molecule Inhibitors of Glutaminyl Cyclase and Isoglutaminyl Cyclase for Alzheimer's Disease

“…After treatment with compound 17 , QC activities and the conversion of β‐amyloids to pyroglutamate‐modified β‐amyloids were inhibited in PC12 cells. A total of 28 genes and a couple of chaperones were observed to be regulated …”