title: SLM, a novel carbazole-based fluorophore attenuates okadaic acid-induced tau hyperphosphorylation via down-regulating GSK-3β activity in SH-SY5Y cells.
abstract: Phosphorylated tau dissociates from microtubules and aggregates to form neurofibrillary tangles resulting in neuronal toxicity and cognitive deficits. Attenuating tau hyperphosphorylation is considered as an effective therapeutic approach for Alzheimer's disease (AD). From our previous study, SLM, a carbazole-based fluorophore prevents Aβ aggregation, reduced glycogen synthase kinase-3β (GSK-3β) activity and tau hyperphosphorylation in triple transgenic mouse model of AD. However, the mechanism by which SLM attenuates tau hyperphosphorylation warrants further investigation. In the current study, we intend to evaluate the effects of SLM against okadaic acid (OA)-induced tau hyperphosphorylation and microtubules instability in human neuroblastoma (SH-SY5Y) cells. The results showed that, SLM reduced the OA-induced cell neurotoxicity and tau hyperphosphorylation in SH-SY5Y cells. SLM treatment down-regulated GSK-3β activity. However, in the presence of GSK-3β inhibitor (SB216763, 10μM), SLM treatment could not reduce GSK-3β activity and tau hyperphosphorylation as compared with SB216763 treatment alone. Furthermore, SLM treatment also ameliorated OA-induced microtubules instability and cytoskeleton damage. Collectively, SLM attenuated OA-induced tau hyperphosphorylation via down-regulating GSK-3β activity in SH-SY5Y cells. Therefore, this study supports SLM as a potential compound for AD and other tau pathology-related neurodegenerative disorders.
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
authors.forename: Jayasankar
authors.initials: J
authors.lastname: Kosaraju
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China. Electronic address: kintam@umac.mo.
authors.forename: Kin Yip
authors.initials: KY
authors.lastname: Tam
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D009474:Neurons; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019319:Okadaic Acid / Q000494:pharmacology*; D010766:Phosphorylation; D055550:Protein Stability; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D002227:Carbazoles; D007211:Indoles; D008301:Maleimides; D018696:Neuroprotective Agents; C417521:SB 216763; D016875:tau Proteins; D019319:Okadaic Acid; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Alzheimer's disease; Glycogen synthase kinase-3β; Okadaic acid; SLM; Tau hyperphosphorylation