title: Ginkgo biloba extract (Egb761) attenuates zinc-induced tau phosphorylation at Ser262 by regulating GSK3β activity in rat primary cortical neurons.
abstract: In the brain, an excessive amount of zinc promotes the deposition of β-amyloid proteins and the intraneuronal accumulation of neurofibrillary tangles composed of hyperphosphorylated tau proteins. These consequences are key neuropathological traits that reflect Alzheimer's disease. Egb761, a standardized Ginkgo biloba extract, is a powerful antioxidant known to exhibit neuroprotective actions. In this study, we investigated whether Egb761 can counteract the zinc-induced tau phosphorylation in rat primary cortical neurons. To determine the modification of tau phosphorylation by Egb761 treatment, we conducted Western blot analyses, MTT assay, ROS measurements and immunocytochemistry. We found that zinc-induced tau phosphorylation occurred at Ser262 in a time- and dose-dependent manner while other tau sites were not phosphorylated. Tau phosphorylation at Ser262 was increased 30 min after zinc treatment and peaked 3 h after zinc treatment (control: 100 ± 1.2%, 30 min: 253 ± 2.24%, 3 h: 373 ± 1.3%). Interestingly, Egb761 treatment attenuated the zinc-induced tau hyperphosphorylation at Ser262 in a concentration-dependent manner while the antioxidant N-acetylcysteine showed a similar effect. Furthermore, Egb761 prevented the zinc-induced activation of p38 MAPK and GSK3β, as well as the zinc-induced increase in ROS production and neuronal cell death. Lithium chloride also inhibited the zinc-induced tau phosphorylation but did not affect ROS levels. These results suggest the potential of Egb761 for inhibiting the zinc-induced tau phosphorylation at Ser262 through its anti-oxidative actions involving the regulation of GSK3β. Therefore, Egb761 may be a candidate for the treatment of tauopathy present in neurological disorders such as Alzheimer's disease.
authors.affiliation: Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, 120 Neungdong-ro Gwangjin-gu, Seoul 143-701, Korea. alzdoc@naver.com.
authors.forename: Kyoung Ja
authors.initials: KJ
authors.lastname: Kwon
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Lee
authors.forename: Kyu Suk
authors.initials: KS
authors.lastname: Cho
authors.forename: Du-Hyong
authors.initials: DH
authors.lastname: Cho
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002712:Chlorides / Q000037:antagonists & inhibitors / Q000633:toxicity; D004622:Embryo, Mammalian / Q000166:cytology; D020441:Ginkgo biloba; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007700:Kinetics; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D017967:Zinc Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity; D016875:tau Proteins / Q000378:metabolism*; D000096983:Ginkgo Extract
chemical_list: D000975:Antioxidants; D002712:Chlorides; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D016877:Oxidants; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D012694:Serine; D017967:Zinc Compounds; D016875:tau Proteins; C489131:Mapt protein, rat; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract; C016837:zinc chloride; C000605508:Gsk3b protein, rat