Characteristics of TBS-extractable hyperphosphorylated tau species: Aggregation intermediates in rTg4510 mouse brain

Naruhiko Sahara, Michael De Ture, Yan Ren, Abdul Shukkur Ebrahim, Dongcheul Kang, Joshua Knight, Christiane Volbracht, Jan Torleif Pedersen, Dennis W. Dickson, Shu Hui Yen, Jada Lewis

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Conditional overexpression of four-repeat human tau containing the P301L missense mutation in the rTg4510 mouse model of tauopathy leads to progressive accumulation of neurofibrillary tangles and hyperphosphorylated, sarkosyl-insoluble tau species, which are biochemically comparable to abnormal tau characteristic of hereditary tauopathies termed FTDP-17. To fully understand the impact of tau species at different stages of self-assembly on neurodegeneration, we fractionated rTg4510 brain representing several stages of tauopathy to obtain TBS-extractable (S1), high salt/sarkosyl-extractable (S3), and sarkosyl-insoluble (P3) fractions. Under reducing condition, the S1 fraction was demonstrated by western blotting to contain both 50-60 kDa normally-sized and 64 kDa tau. Both are thermo-stable, but the 64 kDa tau showed a higher degree of phosphorylation. Under non-reducing condition, nearly all TBS-extractable 64 kDa tau were detected as ∼130 kDa species consistent with the size of dimer. Quantitative analysis showed ∼80 times more 64 kDa tau in S1 than P3 fraction. Immunoelectron microscopy revealed tau-positive granules/short filaments in S1 fraction. These structures displayed MC1 immunoreactivities indicative of conformational/pathological change of tau. MC1 immunoreactivity was detected by dot blotting in samples from 2.5 month-old mice, whereas Ab39 immunoreactivity indicative of late stages of tau assembly was detected only in P3 fraction. Quantitative analysis also demonstrated a significant inverse correlation between brain weight and 64 kDa tau, but the level of TBS-extractable 64 kDa tau reflects neurodegeneration better than that of sarkosyl-insoluble 64 kDa tau. Together, the findings suggest that TBS-extractable 64 kDa tau production is a potential target for therapeutic intervention of tauopathies.

Original languageEnglish (US)
Pages (from-to)249-263
Number of pages15
JournalJournal of Alzheimer's Disease
Volume33
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Dimer
  • FTDP-17
  • hyperphosphorylation
  • tau protein
  • tauopathy
  • transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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    Sahara, N., De Ture, M., Ren, Y., Ebrahim, A. S., Kang, D., Knight, J., Volbracht, C., Pedersen, J. T., Dickson, D. W., Yen, S. H., & Lewis, J. (2013). Characteristics of TBS-extractable hyperphosphorylated tau species: Aggregation intermediates in rTg4510 mouse brain. Journal of Alzheimer's Disease, 33(1), 249-263. https://doi.org/10.3233/JAD-2012-121093