Abstract
Rationale
Tau hyperphosphorylation and aggregation is considered as a main pathological mechanism underlying Alzheimer’s disease (AD). Rose Bengal (RB) is a synthetic dye used for disease diagnosis, which was reported to inhibit tau toxicity via inhibiting tau aggregation in Drosophila. However, it was unknown if RB could produce anti-AD effects in rodents.
Objectives
The research aimed to investigate if and how RB could prevent β-amyloid (Aβ) oligomers-induced tau hyperphosphorylation in rodents.
Methods and results
RB was tested in vitro (0.3–1 μM) and prevented Aβ oligomers-induced tau hyperphosphorylation in PC12 cells. Moreover, RB (10–30 mg/kg, i.p.) effectively attenuated cognitive impairments induced by Aβ oligomers in mice. Western blotting analysis demonstrated that RB significantly increased the expression of pSer473-Akt, pSer9-glycogen synthase kinase-3β (GSK3β) and reduced the expression of cyclin-dependent kinase 5 (CDK5) both in vitro and in vivo. Molecular docking analysis suggested that RB might directly interact with GSK3β and CDK5 by acting on ATP binding sites. Gene Ontology enrichment analysis indicated that RB might act on protein phosphorylation pathways to inhibit tau hyperphosphorylation.
Conclusions
RB was shown to inhibit tau neurotoxicity at least partially via inhibiting the activity of GSK3β and CDK5, which is a novel neuroprotective mechanism besides the inhibition of tau aggregation. As tau hyperphosphorylation is an important target for AD therapy, this study also provided support for investigating the drug repurposing of RB as an anti-AD drug candidate.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81870853), Natural Science Foundation of Zhejiang Province (LY21H090002, LY19H25001), Major program of Ningbo Science and Technology Innovation 2025 (2019B10067), Natural Science Foundation of Ningbo (2013A610247, 202003N4247), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (2019RC266, 2021KY1043), Ningbo medical science and technology project (2019Y16), The Affiliated Hospital of Medical School of Ningbo University Youth Talent Cultivation Program (FYQM-LC-202002), LiDakSum Marine Biopharmaceutical Development Fund, and the K. C. Wong Magna Fund in Ningbo University. We thank technical support from the Core Facilities, Ningbo University School of Medicine. We would like to express our gratitude to all members of the College Student Innovation Team in Dr. Cui Wei’s Lab.
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Mou, CY., Xie, YF., Wei, JX. et al. Rose Bengal inhibits β-amyloid oligomers-induced tau hyperphosphorylation via acting on Akt and CDK5 kinases. Psychopharmacology 239, 3579–3593 (2022). https://doi.org/10.1007/s00213-022-06232-3
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DOI: https://doi.org/10.1007/s00213-022-06232-3