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Interaction of 14-3-3ζ with Microtubule-Associated Protein Tau within Alzheimer’s Disease Neurofibrillary Tangles

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† The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte-Sainte-Catherine Road, Montreal, Quebec, Canada H3T 1E2
‡ Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 0G4
§ Department of Pathology, University of Montreal, Montreal, Quebec, Canada H3T 1E2
*Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte-Sainte-Catherine Rd., Montreal, Quebec, Canada H3T 1E2. Telephone: (514) 340-8222, ext. 4866. Fax: (514) 340-7502. E-mail: [email protected]
Cite this: Biochemistry 2013, 52, 37, 6445–6455
Publication Date (Web):August 20, 2013
https://doi.org/10.1021/bi400442d
Copyright © 2013 American Chemical Society
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    Abstract

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    Alzheimer’s disease (AD) is characterized by the presence of abnormal, straight filaments and paired helical filaments (PHFs) that are coated with amorphous aggregates. When PHFs are treated with alkali, they untwist and form filaments with a ribbonlike morphology. Tau protein is the major component of all of these ultrastructures. 14-3-3ζ is present in NFTs and is significantly upregulated in AD brain. The molecular basis of the association of 14-3-3ζ within NFTs and the pathological significance of its association are not known. In this study, we have found that 14-3-3ζ is copurified and co-immunoprecipitates with tau from NFTs of AD brain extract. In vitro, tau binds to both phosphorylated and nonphosphorylated tau. When incubated with 14-3-3ζ, tau forms amorphous aggregates, single-stranded, straight filaments, ribbonlike filaments, and PHF-like filaments, all of which resemble the corresponding ultrastructures found in AD brain. Immuno-electron microscopy determined that both tau and 14-3-3ζ are present in these ultrastructures and that they are formed in an incubation time-dependent manner. Amorphous aggregates are formed first. As the incubation time increases, the size of amorphous aggregates increases and they are incorporated into single-stranded filaments. Single-stranded filaments laterally associate to form double-stranded, ribbonlike, and PHF-like filaments. Both tau and phosphorylated tau aggregate in a similar manner when they are incubated with 14-3-3ζ. Our data suggest that 14-3-3ζ has a role in the fibrillization of tau in AD brain, and that tau phosphorylation does not affect 14-3-3ζ-induced tau aggregation.

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