title: Perinatal exposure to lead (Pb) promotes Tau phosphorylation in the rat brain in a GSK-3β and CDK5 dependent manner: Relevance to neurological disorders.
abstract: Hyperphosphorylation of Tau is involved in the pathomechanism of neurological disorders such as Alzheimer's, Parkinson's diseases as well as Autism. Epidemiological data suggest the significance of early life exposure to lead (Pb) in etiology of disorders affecting brain function. However, the precise mechanisms by which Pb exerts neurotoxic effects are not fully elucidated. The purpose of this study was to evaluate the effect of perinatal exposure to low dose of Pb on the Tau pathology in the developing rat brain. Furthermore, the involvement of two major Tau-kinases: glycogen synthase kinase-3 beta (GSK-3β) and cyclin-dependent kinase 5 (CDK5) in Pb-induced Tau modification was evaluated. Pregnant female rats were divided into control and Pb-treated group. The control animals were maintained on drinking water while females from the Pb-treated group received 0.1% lead acetate (PbAc) in drinking water, starting from the first day of gestation until weaning of the offspring. During the feeding of pups, mothers from the Pb-treated group were still receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-day old pups were sacrificed and Tau mRNA and protein level as well as Tau phosphorylation were analyzed in forebrain cortex (FC), cerebellum (C) and hippocampus (H). Concomitantly, we examined the effect of Pb exposure on GSK-3β and CDK5 activation. Our data revealed that pre- and neonatal exposure to Pb (concentration of Pb in whole blood below 10μg/dL, considered safe for humans) caused significant increase in the phosphorylation of Tau at Ser396 and Ser199/202 with parallel rise in the level of total Tau protein in FC and C. Tau hyperphosphorylation in Pb-treated animals was accompanied by elevated activity of GSK-3β and CDK5. Western blot analysis revealed activation of GSK-3β in FC and C as well as CDK5 in C, via increased phosphorylation of Tyr-216 and calpain-dependent p25 formation, respectively. In conclusion, perinatal exposure to Pb up-regulates Tau protein level and induces Tau hyperphosphorylation in the rat brain cortex and cerebellum. We suggest that neurotoxic effect of Pb might be mediated, at least in part, by GSK-3β and CDK5-dependent Tau hyperphosphorylation, which may lead to the impairment of cytoskeleton stability and neuronal dysfunction.
authors.affiliation: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland. Electronic address: magy80@gmail.com.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gąssowska
authors.affiliation: Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland. Electronic address: ika@pum.edu.pl.
authors.forename: Irena
authors.initials: I
authors.lastname: Baranowska-Bosiacka
authors.affiliation: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Moczydłowska
authors.affiliation: Department of Physiology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Tarnowski
authors.affiliation: Department of Histology and Embryology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Pilutin
authors.affiliation: Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24, 71-460 Szczecin, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Gutowska
authors.affiliation: Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
authors.forename: Lidia
authors.initials: L
authors.lastname: Strużyńska
authors.affiliation: Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Chlubek
authors.affiliation: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Adamczyk
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007854:Lead / Q000633:toxicity*; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D007854:Lead; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; C495907:Cdk5 protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: CDK5; GSK-3β; Hyperphosphorylation; Lead neurotoxicity; Rat brain; Tau protein