Discovery and characterization of stable and toxic Tau/phospholipid oligomeric complexes

Nadine Ait-Bouziad, Guohua Lv, Anne-Laure Mahul-Mellier, Shifeng Xiao, Gizem Zorludemir, David Eliezer, Thomas Walz and Hilal A. Lashuel ()
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Nadine Ait-Bouziad: Ecole Polytechnique Fédérale de Lausanne
Guohua Lv: Weill Cornell Medicine
Anne-Laure Mahul-Mellier: Ecole Polytechnique Fédérale de Lausanne
Shifeng Xiao: Weill Cornell Medicine
Gizem Zorludemir: Ecole Polytechnique Fédérale de Lausanne
David Eliezer: Weill Cornell Medicine
Thomas Walz: Rockefeller University
Hilal A. Lashuel: Ecole Polytechnique Fédérale de Lausanne

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract The microtubule-associated protein Tau plays a central role in the pathogenesis of Alzheimer’s disease. Although Tau interaction with membranes is thought to affect some of its physiological functions and its aggregation properties, the sequence determinants and the structural and functional consequences of such interactions remain poorly understood. Here, we report that the interaction of Tau with vesicles results in the formation of highly stable protein/phospholipid complexes. These complexes are toxic to primary hippocampal cultures and are detected by MC-1, an antibody recognizing pathological Tau conformations. The core of these complexes is comprised of the PHF6* and PHF6 hexapeptide motifs, the latter in a β-strand conformation. Studies using Tau-derived peptides enabled the design of mutants that disrupt Tau interactions with phospholipids without interfering with its ability to form fibrils, thus providing powerful tools for uncoupling these processes and investigating the role of membrane interactions in regulating Tau function, aggregation and toxicity.

Date: 2017
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DOI: 10.1038/s41467-017-01575-4

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