Identification of oligomers at early stages of tau aggregation in Alzheimer's disease

Cristian A. Lasagna-Reeves, Diana L. Castillo-Carranza, Urmi Sengupta, Jose Sarmiento, Juan Troncoso, George R. Jackson, Rakez Kayed

Research output: Contribution to journalArticle

214 Scopus citations

Abstract

Neurofibrillary tangles (NFTs) are a pathological hallmark of Alzheimer's disease (AD); however, the relationship between NFTs and disease progression remains controversial. Analyses of tau animal models suggest that phenotypes coincide with accumulation of soluble aggregated tau species but not the accumulation of NFTs. The pathological role of prefilamentous tau aggregates, e.g., tau oligomeric intermediates, is poorly understood, in part because of methodological challenges. Here, we engineered a novel tau oligomer-specific antibody, T22, and used it to elucidate the temporal course and biochemical features of oligomers during NFT development in AD brain. We found that tau oligomers in human AD brain samples were 4-fold higher than those in the controls. We also revealed the role of oligomeric tau conformers in pretangles, neuritic plaques, and neuropil threads in the frontal cortex tissue from AD brains; this analysis uncovers a consistent code that governs tau oligomerization with regard to degree of neuronal cytopathology. These data are the first to characterize the role of tau oligomers in the natural history of NFTs, and they highlight the suitability of tau oligomers as therapeutic targets in AD and related tauopathies.

Original languageEnglish (US)
Pages (from-to)1946-1959
Number of pages14
JournalFASEB Journal
Volume26
Issue number5
DOIs
StatePublished - May 1 2012
Externally publishedYes

Keywords

  • Conformational antibodies
  • Neurodegeneration
  • Protein misfolding
  • Tauopathies

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Sarmiento, J., Troncoso, J., Jackson, G. R., & Kayed, R. (2012). Identification of oligomers at early stages of tau aggregation in Alzheimer's disease. FASEB Journal, 26(5), 1946-1959. https://doi.org/10.1096/fj.11-199851