Open Access

A novel non‑selective atypical PKC agonist could protect neuronal cell line from Aβ‑oligomer induced toxicity by suppressing Aβ generation

  • Authors:
    • Dongmei Zou
    • Qian Li
    • Wenyang Pan
    • Peng Chen
    • Miao Sun
    • Xiaofeng Bao
  • View Affiliations

  • Published online on: March 2, 2022     https://doi.org/10.3892/mmr.2022.12669
  • Article Number: 153
  • Copyright: © Zou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Atypical protein kinase C (aPKCs) serve key functions in embryonic development by regulating apical‑basal polarity. Previous studies have shed light on their roles during adulthood, especially in the development of Alzheimer's disease (AD). Although the crystal structure of PKCι has been resolved, an agonist of aPKCs remains to be discovered. In the present study, by using the Discovery Studio program and LibDock methodology, a small molecule library (K66‑X4436 KINA Set) of compounds were screened for potential binding to PKCι. Subsequently, the computational docking results were validated using affinity selection‑mass spectrometry, before in vitro kinase activity was used to determine the function of the hit compounds. A cell‑based model assay that can mimic the pathology of AD was then established and used to assess the function of these hit compounds. As a result, the aPKC agonist Z640 was identified, which could bind to PKCι in silico, in vitro and in this cell‑based model. Z640 was further confirmed as a non‑selective aPKC agonist that can activate the kinase activity of both PKCι and PKCζ. In the cell‑based assay, Z640 was found to protect neuronal cell lines from amyloid‑β (Aβ) oligomer‑induced cell death by reducing reactive oxygen species production and restore mitochondrial function. In addition, Z640 could reduce Aβ40 generation in a dose‑dependent manner and shift amyloid precursor protein processing towards the non‑amyloid pathway. To conclude, the present study is the first, to the best of the authors' knowledge to identify an aPKC agonist by combining computer‑assisted drug discovery and cell‑based assays. The present study also revealed that aPKC agonists have therapeutic potential for the treatment of AD.
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May-2022
Volume 25 Issue 5

Print ISSN: 1791-2997
Online ISSN:1791-3004

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Spandidos Publications style
Zou D, Li Q, Pan W, Chen P, Sun M and Bao X: A novel non‑selective atypical PKC agonist could protect neuronal cell line from Aβ‑oligomer induced toxicity by suppressing Aβ generation. Mol Med Rep 25: 153, 2022
APA
Zou, D., Li, Q., Pan, W., Chen, P., Sun, M., & Bao, X. (2022). A novel non‑selective atypical PKC agonist could protect neuronal cell line from Aβ‑oligomer induced toxicity by suppressing Aβ generation. Molecular Medicine Reports, 25, 153. https://doi.org/10.3892/mmr.2022.12669
MLA
Zou, D., Li, Q., Pan, W., Chen, P., Sun, M., Bao, X."A novel non‑selective atypical PKC agonist could protect neuronal cell line from Aβ‑oligomer induced toxicity by suppressing Aβ generation". Molecular Medicine Reports 25.5 (2022): 153.
Chicago
Zou, D., Li, Q., Pan, W., Chen, P., Sun, M., Bao, X."A novel non‑selective atypical PKC agonist could protect neuronal cell line from Aβ‑oligomer induced toxicity by suppressing Aβ generation". Molecular Medicine Reports 25, no. 5 (2022): 153. https://doi.org/10.3892/mmr.2022.12669