Soluble oligomers from a non-disease related protein mimic Aβ-induced tau hyperphosphorylation and neurodegeneration

Authors

  • Marcelo N. N. Vieira,

    1. Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
    2. Programa de Ciências Morfológicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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  • Letícia Forny-Germano,

    1. Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
    2. Departamento de Anatomia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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  • Leonardo M. Saraiva,

    1. Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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  • Adriano Sebollela,

    1. Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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  • Ana M. Blanco Martinez,

    1. Departamento de Histologia e Embriologia, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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  • Jean-Christophe Houzel,

    1. Departamento de Anatomia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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  • Fernanda G. De Felice,

    1. Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
    2. Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, USA
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  • Sérgio T. Ferreira

    1. Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Address correspondence and reprint requests to Fernanda G. De Felice or Sergio T. Ferreira, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil.
E-mails: felice@bioqmed.ufrj.br (FGF) or ferreira@bioqmed.ufrj.br (STF)

Abstract

Protein aggregation and amyloid accumulation in different tissues are associated with cellular dysfunction and toxicity in important human pathologies, including Alzheimer’s disease and various forms of systemic amyloidosis. Soluble oligomers formed at the early stages of protein aggregation have been increasingly recognized as the main toxic species in amyloid diseases. To gain insight into the mechanisms of toxicity instigated by soluble protein oligomers, we have investigated the aggregation of hen egg white lysozyme (HEWL), a normally harmless protein. HEWL initially aggregates into β-sheet rich, roughly spherical oligomers which appear to convert with time into protofibrils and mature amyloid fibrils. HEWL oligomers are potently neurotoxic to rat cortical neurons in culture, while mature amyloid fibrils are little or non-toxic. Interestingly, when added to cortical neuronal cultures HEWL oligomers induce tau hyperphosphorylation at epitopes that are characteristically phosphorylated in neurons exposed to soluble oligomers of the amyloid-β peptide. Furthermore, injection of HEWL oligomers in the cerebral cortices of adult rats induces extensive neurodegeneration in different brain areas. These results show that soluble oligomers from a non-disease related protein can mimic specific neuronal pathologies thought to be induced by soluble amyloid-β peptide oligomers in Alzheimer’s disease and support the notion that amyloid oligomers from different proteins may share common structural determinants that would explain their generic cytotoxicities.

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