title: Translocation of PKC by yessotoxin in an in vitro model of Alzheimer's disease with improvement of tau and β-amyloid pathology.
abstract: Yessotoxin is a marine phycotoxin that induces motor alterations in mice after intraperitoneal injection. In primary cortical neurons, yessotoxin treatment induced a caspase-independent cell death with an IC50 of 4.27 nM. This neurotoxicity was enhanced by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and partially blocked by amiloride. Unlike previous studies, yessotoxin did not increase cyclic adenosine monophosphate levels or produce any change in phosphodiesterase 4 steady state expression in triple transgenic neurons. Since phosphodiesterases (PDEs) are engaged in learning and memory, we studied the in vitro effect of the toxin against Alzheimer's disease hallmarks and observed that pretreatment of cortical 3xTg-AD neurons with a low nanomolar concentration of yessotoxin showed a decrease expression of hyperphosphorylated tau isoforms and intracellular accumulation of amyloid-beta. These effects were accompanied with an increase in the level of the inactive isoform of the glycogen synthase kinase 3 and also by a translocation of protein kinase C from cytosol to membrane, pointing to its activation. In fact, inhibition of protein kinase C with GF109203X blocked the effect of yessotoxin over tau protein. The data presented here shows that 1 nM yessotoxin activates protein kinase C with beneficial effects over the main Alzheimer's disease hallmarks, tau and Aβ, in a cellular model obtained from 3xTg-AD fetuses.
authors.affiliation: Departamento de Farmacología and ‡Departamento de Fisiología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Alonso
authors.forename: Carmen
authors.initials: C
authors.lastname: Vale
authors.forename: Mercedes R
authors.initials: MR
authors.lastname: Vieytes
authors.forename: Luis M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008978:Mollusk Venoms; D035964:Oxocins / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D007211:Indoles; D008301:Maleimides; D008978:Mollusk Venoms; D035964:Oxocins; D016875:tau Proteins; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3; C070515:bisindolylmaleimide I; C066632:yessotoxin