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Faseb Journal 2012, Vol. 26 (5) :1946 -1959 doi:10.1096/fj.11-199851 <<-上一篇 下一篇 ->>
Identification of oligomers at early stages of tau aggregation in;Alzheimer's disease
Lasagna-Reeves, Cristian A.;Castillo-Carranza, Diana L.;Sengupta, Urmi;Sarmiento, Jose;Troncoso, Juan;Jackson, George R.;Kayed, Rakez
[Lasagna-Reeves, Cristian A.; Castillo-Carranza, Diana L.; Sengupta, Urmi; Jackson, George R.; Kayed, Rakez] Univ Texas Med Branch, George P & Cynthia Woods Mitchell Ctr Neurodegene, Galveston, TX 77555 USA.;[Lasagna-Reeves, Cristian A.; Castillo-Carranza, Diana L.; Sengupta, Urmi; Jackson, George R.; Kayed, Rakez] Univ Texas Med Branch, Dept Neurol, Galveston, TX USA.;[Sarmiento, Jose; Jackson, George R.; Kayed, Rakez] Univ Texas Med Branch, Dept Neurosci & Cell Biol, Galveston, TX USA.;[Troncoso, Juan] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA.
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.-Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Troncoso, J., Jackson, G. R., Kayed, R. Identification of oligomers at early stages of tau aggregation in Alzheimer's disease. FASEB J. 26, 1946-1959 (2012). www.fasebj.org
Keywords: PAIRED HELICAL FILAMENTS GLYCOGEN-SYNTHASE KINASE-3-BETA MILD COGNITIVE IMPAIRMENT RESONANCE ENERGY-TRANSFER FULL-LENGTH TAU NEUROFIBRILLARY TANGLES MOUSE MODEL CEREBROSPINAL-FLUID EXTRACELLULAR TAU TRANSGENIC MICE
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