title: Wnt co-receptor LRP5/6 overexpression confers protection against hydrogen peroxide-induced neurotoxicity and reduces tau phosphorylation in SH-SY5Y cells.
abstract: Emerging studies have suggested the involvement of dysregulated Wnt/β-catenin cascade in the etiology of Alzheimer's disease (AD). Recently, genetic variations in Wnt co-receptor low density lipoprotein receptor-related protein (LRP) 6 causing reduced Wnt signaling has been linked to late-onset AD. Here, we hypothesized that overexpression of Wnt co-receptors LRP5 and LRP6 would serve as an effective new approach in reducing neurotoxicity induced by oxidative stress and decreasing tau phosphorylation in SH-SY5Y human neuroblastoma cells. Our results showed that overexpression of LRP5 and LRP6 in SH-SY5Y cells activates Wnt signaling and downstream proliferation genes, whereas knockdown of the co-receptors represses Wnt signaling and the transcription of proliferative markers. We further demonstrated that overexpression of LRP5 and LRP6 protects SH-SY5Y from cell death caused by hydrogen peroxide-induced oxidative stress, inhibits GSK3β activity and subsequently reduces tau phosphorylation. Together, our findings suggest that rescuing LRP5/6-mediated Wnt signaling improves neuronal cell survival and reduces tau phosphorylation, which support the hypothesis that Wnt signaling might be an attractive therapeutic strategy for managing AD.
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Luqi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Priti
authors.initials: P
authors.lastname: Bahety
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address: phaeplr@nus.edu.sg.
authors.forename: Pui Lai Rachel
authors.initials: PL
authors.lastname: Ee
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D016875:tau Proteins; D006861:Hydrogen Peroxide
keywords: Alzheimer's disease; Hydrogen peroxide; Low density lipoprotein receptor-related protein 5/6; Neurotoxicity; Reactive oxygen species; Wnt signaling