Chen-Ye Mou1,2, Yan-Fei Xie2, Jia-Xin Wei1,3, Qi-Yao Wang2, Jing-Yang Le2, Yong-Jie Bao2, Pan-Pan Zhang2, Yue-Chun Mao2, Xing-Han Huang2, Han-Bo Pan2, C Benjamin Naman3, Lin Liu1, Hong-Ze Liang4, Xiang Wu1, Jia Xu1,2, Wei Cui5,6. 1. The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315211, China. 2. Translational Medicine Center of Pain, Emotion and Cognition, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China. 3. Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, School of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, 315211, China. 4. School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, 315211, China. 5. The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315211, China. cuiwei@nbu.edu.cn. 6. Translational Medicine Center of Pain, Emotion and Cognition, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China. cuiwei@nbu.edu.cn.
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.
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.
Authors: Luis Aragão Gomes; Valerie Uytterhoeven; Diego Lopez-Sanmartin; Sandra O Tomé; Thomas Tousseyn; Rik Vandenberghe; Mathieu Vandenbulcke; Christine A F von Arnim; Patrik Verstreken; Dietmar Rudolf Thal Journal: Acta Neuropathol Date: 2021-01-11 Impact factor: 17.088