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Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Inhibition of the PERK-Dependent Unfolded Protein Response Signaling Pathway Involved in the Pathogenesis of Alzheimer’s Disease

Author(s): Wioletta Rozpędek, Dariusz Pytel, Tomasz Popławski, Anna Walczak, Kinga Gradzik, Adam Wawrzynkiewicz, Radosław Wojtczak, Bartosz Mucha, John Alan Diehl and Ireneusz Majsterek*

Volume 16, Issue 3, 2019

Page: [209 - 218] Pages: 10

DOI: 10.2174/1567205016666190228121157

Price: $65


Objectives: There is a body of evidence that neurodegenerative disease entities are directly correlated with the perturbations on the molecular level. Hence, the ER stress-mediated Unfolded Protein Response (UPR) is activated resulting in PERK-dependent phosphorylation of the Eukaryotic initiation factor 2 (eIF2α). Thus, the levels of ATF4 and CHOP proteins are significantly increased, which subsequently switches the pro-adaptive branch of the UPR into the pro-apoptotic directly leading to neuronal loss and initiation of the neurodegenerative process. The aim of the presented study was the evaluation of the biological activity of highly specific, small-molecule inhibitors of the PERKdependent UPR signaling pathway.

Methods: The study was conducted on rat astrocytic DI TNC1 cell line. The level of p-eIF2α was measured by Western blot technique, the cytotoxicity of the investigated compound was assessed by the MTT assay and using the FITC-conjugated Annexin V (Annexin V-FITC) to indicate apoptosis and propidium iodide (PI) to indicate necrosis. The effect of tested compound on cell cycle progression was measured by flow cytometry, where the PI-labelled nuclei were analysed for DNA content.

Results: As a result one of the investigated compound LDN-0060609 triggers a significant inhibition of the eIF2α phosphorylation in DI TNC1 cell line. Moreover, we showed that compound LDN-0060609 is non-cytotoxic and has no effect on cell cycle progression.

Conclusion: In conclusion, LDN-0060609 may constitute a novel, targeted treatment approach against neurodegenerative diseases, including Alzheimer’s disease (AD), where pathogenesis and progression are closely associated with the overactivation of the PERK-dependent UPR signaling pathway.

Keywords: PERK, eIF2α, PERK inhibitors, neurodegeneration, Alzheimer's disease, apoptosis.

Erratum In:
Erratum: Inhibition of the PERK-dependent Unfolded Protein Response Signaling Pathway Involved in the Pathogenesis of Alzheimer’s Disease

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