title: Identification of oligomers at early stages of tau aggregation in Alzheimer's disease.
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.
authors.affiliation: University of Texas Medical Branch, 301 University Blvd., Medical Research Building, Room 10.138C, Galveston, TX, USA.
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Lasagna-Reeves
authors.forename: Diana L
authors.initials: DL
authors.lastname: Castillo-Carranza
authors.forename: Urmi
authors.initials: U
authors.lastname: Sengupta
authors.forename: Jose
authors.initials: J
authors.lastname: Sarmiento
authors.forename: Juan
authors.initials: J
authors.lastname: Troncoso
authors.forename: George R
authors.initials: GR
authors.lastname: Jackson
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000906:Antibodies / Q000276:immunology; D001704:Biopolymers / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D031541:Fluorescence Resonance Energy Transfer; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D010766:Phosphorylation; D054875:Ubiquitination; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D001704:Biopolymers; D016875:tau Proteins