Intraneuronal Tau Misfolding Induced by Extracellular Amyloid-β Oligomers

Article type: Research Article

Authors: Rudenko, Lauren K.^a | Wallrabe, Horst^{a; b} | Periasamy, Ammasi^{a; b} | Siller, Karsten H.^c | Svindrych, Zdenek^d | Seward, Matthew E.^{a; e} | Best, Merci N.^a | Bloom, George S.^{a; e; f; *}

Affiliations: [a] Department of Biology, University of Virginia, Charlottesville, VA, USA | [b] W.M. Keck Center for Cellular Imaging, University of Virginia, Charlottesville, VA, USA | [c] Advanced Research Computing Services, University of Virginia, Charlottesville, VA, USA | [d] Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA | [e] Department of Cell Biology, University of Virginia, Charlottesville, VA, USA | [f] Department of Neuroscience, University of Virginia, Charlottesville, VA, USA

Correspondence: [*] Correspondence to: George S. Bloom, Department of Biology, University of Virginia, PO Box 400328, Charlottesville, VA 22904-4328, USA. Tel.: +1 434 243 3543; E-mail: gsb4g@virginia.edu.

Abstract: Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer’s disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might precede formation of toxic tau oligomers and filaments, like those found in AD brain. While there are many ways to monitor tau aggregation, methods to monitor changes in tau folding are not well established. Using full length human 2N4R tau doubly labeled with the Förster resonance energy transfer (FRET) compatible fluorescent proteins, Venus and Teal, on the N- and C-termini, respectively (Venus-Tau-Teal), intensity and lifetime FRET measurements were able to distinguish folded from unfolded tau in living cells independently of tau-tau intermolecular interactions. When expression was restricted to low levels in which tau-tau aggregation was minimized, Venus-Tau-Teal was sensitive to microtubule binding, phosphorylation, and pathogenic oligomers. Of particular interest is our finding that amyloid-β oligomers (AβOs) trigger Venus-Tau-Teal unfolding in cultured mouse neurons. We thus provide direct experimental evidence that AβOs convert normally folded tau into a conformation thought to predominate in toxic tau aggregates. This finding provides further evidence for a mechanistic connection between Aβ and tau at seminal stages of AD pathogenesis.

Keywords: Alzheimer’s disease, amyloid-β, FRET, tauopathies, tau

DOI: 10.3233/JAD-190226

Journal: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1125-1138, 2019