TAILIEUCHUNG - Báo cáo Y học: Formation of aberrant phosphotau fibrillar polymers in neural cultured cells

Here we show, for the ®rst time, thein vitro formation of ®lamentous aggregates of phosphorylated tau protein in SH-SY5Y human neuroblastoma cells. The formation of suchaberrant aggregates, similar to thoseoccurringinvivoin Alzheimer's disease and other tauopathies, requires okadaic acid, a phosphatase inhibitor, to increase the level of phos-phorylated tau, and hydroxynonenal, a product of oxidative stress that selectively adducts and modi®es phosphorylated tau. | Eur. J. Biochem. 269 1484-1489 2002 FEBS 2002 Formation of aberrant phosphotau brillar polymers in neural cultured cells Mar Perez1 Felix Hernandez1 Alberto Gomez-Ramos1 Mark Smith2 George Perry2 and Jesus Avila1 1 Centro de Biologia Molecular CSIC UAM Facultad de Ciencias. Universidad Autonoma de Madrid Spain institute of Pathology Case Western Reserve University Cleveland OH USA Here we show for the first time the in vitro formation of filamentous aggregates of phosphorylated tau protein in SH-SY5Y human neuroblastoma cells. The formation of such aberrant aggregates similar to those occurring in vivo in Alzheimer s disease and other tauopathies requires okadaic acid a phosphatase inhibitor to increase the level of phosphorylated tau and hydroxynonenal a product of oxidative stress that selectively adducts and modifies phosphorylated tau. Our findings suggest that both phosphorylation and oxidative modification are required for tau filament formation. Importantly the in vitro formation of intracellular tau aggregates could be used as a model of tau polymerization and facilitate the development of novel therapeutic approaches. Keywords Alzheimer s disease tauopathies oxidative stress tau phosphorylation aberrant aggregates. Tauopathies are a heterogeneous group of dementias sharing a common pathological hallmark the presence of aberrant tau filaments or forms of tau 1 2 . Tau is a microtubule-associated protein 3 4 that in pathological situations and in a hyperphosphorylated form 5-8 assembles into fibrillar polymers. The mechanism for that aberrant tau assembly has been widely analyzed by several groups indicating that sulfated glycosaminoglycans or other anionic compounds could favour tau polymerization 9-11 . Another category of agents suggested to alter assembly are fatty acids that can facilitate aggregation either directly 12-15 and or additionally through a reaction with the highly reactive products of lipid oxidation 16 17 . Additionally proteolysis 18 and

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