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Alzheimer's Disease-like Paired Helical Filament Assembly from Truncated Tau Protein Is Independent of Disulfide Crosslinking.

Abstract
Alzheimer's disease is characterized by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into PHFs is not well understood. Here we report that a truncated 95-amino-acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process. Using electron microscopy, circular dichroism and X-ray fiber diffraction, we have characterized the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulfide formation to fibril formation, we have compared the assembly of tau(297-391) under reduced and non-reducing conditions and for truncated tau carrying a C322A substitution. We show that disulfide bond formation inhibits filament assembly and that the C322A variant rapidly forms long and highly ordered PHFs.
AuthorsYoussra K Al-Hilaly, Saskia J Pollack, Devkee M Vadukul, Francesca Citossi, Janet E Rickard, Michael Simpson, John M D Storey, Charles R Harrington, Claude M Wischik, Louise C Serpell
JournalJournal of molecular biology (J Mol Biol) Vol. 429 Issue 23 Pg. 3650-3665 (11 24 2017) ISSN: 1089-8638 [Electronic] Netherlands
PMID28919235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCrown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.
Chemical References
  • Amyloid beta-Peptides
  • Cross-Linking Reagents
  • Disulfides
  • tau Proteins
Topics
  • Alzheimer Disease (metabolism, pathology)
  • Amyloid beta-Peptides (chemistry, metabolism)
  • Brain (metabolism)
  • Cross-Linking Reagents (chemistry, metabolism)
  • Disulfides (chemistry, metabolism)
  • Humans
  • Neurofibrillary Tangles
  • tau Proteins (chemistry, metabolism)

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