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Journal of Biological Chemistry 2012, Vol. 287 (52) :43223 -43233 doi:10.1074/jbc.M112.396176 <<-上一篇 下一篇 ->>
Tau Oligomers Impair Artificial Membrane Integrity and Cellular;Viability
Flach, Katharina;Hilbrich, Isabel;Schiffmann, Andrea;Gaertner, Ulrich;Krueger, Martin;Leonhardt, Marion;Waschipky, Hanka;Wick, Lukas;Arendt, Thomas;Holzer, Max
[Flach, Katharina; Hilbrich, Isabel; Schiffmann, Andrea; Gaertner, Ulrich; Leonhardt, Marion; Arendt, Thomas; Holzer, Max] Univ Leipzig, Fac Med, Dept Mol & Cellular Mech Neurodegenerat, Paul Flechsig Inst Brain Res, D-04109 Leipzig, Germany.;[Krueger, Martin] Inst Anat, D-04103 Leipzig, Germany.;[Waschipky, Hanka] Inst Med Phys & Biophys, D-04107 Leipzig, Germany.;[Wick, Lukas] Helmholtz Ctr Environm Res, Dept Environm Microbiol, D-04318 Leipzig, Germany.
Abstract: The microtubule-associated protein Tau is mainly expressed in neurons, where it binds and stabilizes microtubules. In Alzheimer disease and other tauopathies, Tau protein has a reduced affinity toward microtubules. As a consequence, Tau protein detaches from microtubules and eventually aggregates into beta-sheet-containing filaments. The fibrillization of monomeric Tau to filaments is a multistep process that involves the formation of various aggregates, including spherical and protofibrillar oligomers. Previous concepts, primarily developed for A beta and alpha-synuclein, propose these oligomeric intermediates as the primary cytotoxic species mediating their deleterious effects through membrane permeabilization. In the present study, we thus analyzed whether this concept can also be applied to Tau protein. To this end, viability and membrane integrity were assessed on SH-SY5Y neuroblastoma cells and artificial phospholipid vesicles, treated with Tau monomers, Tau aggregation intermediates, or Tau fibrils. Our findings suggest that oligomeric Tau aggregation intermediates are the most toxic compounds of Tau fibrillogenesis, which effectively decrease cell viability and increase phospholipid vesicle leakage. Our data integrate Tau protein into the class of amyloidogenic proteins and enforce the hypothesis of a common toxicity-mediating mechanism for amyloidogenic proteins.
Keywords: PROTOFIBRILLAR ALPHA-SYNUCLEIN PROTEIN MISFOLDING DISEASES SOLUBLE AMYLOID OLIGOMERS PAIRED HELICAL FILAMENTS BETA-SHEET STRUCTURE ALZHEIMERS-DISEASE PARKINSONS-DISEASE IN-VITRO NEURODEGENERATIVE DISEASES VESICLE PERMEABILIZATION
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