Affiliations: [a] Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA | [b] Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA | [c] Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Correspondence:
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Corresponding author: L.I. Binder, Feinberg School of Medicine, Northwestern University, Dept. of Cell and Molecular Biology, 303 E. Chicago Avenue, Chicago, IL 60611, USA. Tel.: +1 312 503 0823; Fax: +1 312 503 7912; E-mail: l-binder@northwestern.edu.
Abstract: The conformation-dependent antibodies Tau-66 and Alz-50 recognize discontinuous epitopes on the tau molecule (residues 155–244 & 305–314 and 5–15 & 312–322, respectively), thereby defining two distinct conformations. In double- and triple-label immunofluorescence experiments we discovered that specific populations of neurofibrillary tangles display either the Alz-50 or the Tau-66 conformation, but not both. In combination with other antibodies to several domains of the molecule we demonstrate that the conformation recognized by Alz-50 seems to be an early event in the formation of neurofibrillary tangles. This conformation is characterized by the presence of predominantly intact N- and C- termini. By contrast, the Tau-66 conformation is likely a later event in tangle development, being favored in structures containing truncations of both the N- and C- termini. We propose a sequence of events that occurs during the formation and evolution of neurofibrillary tangles based on the initial conformation adopted by tau. In this scheme, the Tau-66 conformation in neurofibrillary tangles may arise from amino and carboxy truncation of tau after it has assumed the Alz-50 conformation. These results indicate that tau structure within the NFT is dynamic in that tau can undergo a "refolding" event following N- and C-terminal truncation.
