title: Characterization of prefibrillar Tau oligomers in vitro and in Alzheimer disease.
abstract: Neurofibrillary tangles, composed of insoluble aggregates of the microtubule-associated protein Tau, are a pathological hallmark of Alzheimer disease (AD) and other tauopathies. However, recent evidence indicates that neuronal dysfunction precedes the formation of these insoluble fibrillar deposits, suggesting that earlier prefibrillar Tau aggregates may be neurotoxic. To determine the composition of these aggregates, we have employed a photochemical cross-linking technique to examine intermolecular interactions of full-length Tau in vitro. Using this method, we demonstrate that dimerization is an early event in the Tau aggregation process and that these dimers self-associate to form larger oligomeric aggregates. Moreover, using these stabilized Tau aggregates as immunogens, we generated a monoclonal antibody that selectively recognizes Tau dimers and higher order oligomeric aggregates but shows little reactivity to Tau filaments in vitro. Immunostaining indicates that these dimers/oligomers are markedly elevated in AD, appearing in early pathological inclusions such as neuropil threads and pretangle neurons as well as colocalizing with other early markers of Tau pathogenesis. Taken as a whole, the work presented herein demonstrates the existence of alternative Tau aggregates that precede formation of fibrillar Tau pathologies and raises the possibility that these hierarchical oligomeric forms of Tau may contribute to neurodegeneration.
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. k-patterson@md.northwestern.edu
authors.forename: Kristina R
authors.initials: KR
authors.lastname: Patterson
authors.forename: Christine
authors.initials: C
authors.lastname: Remmers
authors.forename: Yifan
authors.initials: Y
authors.lastname: Fu
authors.forename: Sarah
authors.initials: S
authors.lastname: Brooker
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Kanaan
authors.forename: Laurel
authors.initials: L
authors.lastname: Vana
authors.forename: Sarah
authors.initials: S
authors.lastname: Ward
authors.forename: Juan F
authors.initials: JF
authors.lastname: Reyes
authors.forename: Keith
authors.initials: K
authors.lastname: Philibert
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Glucksman
authors.forename: Lester I
authors.initials: LI
authors.lastname: Binder
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C054369:MAPT protein, human; D016875:tau Proteins