Alzheimer’s disease seeded tau forms paired helical filaments yet lacks seeding potential
Name
PIIS0021925824022312.pdf
Description
Published version
Size
2.91 MB
Format
Adobe PDF
Checksum (MD5)
0c53626e378dda5137f8860081bcd16a
Author(s)
Duan, Pu
Dregni, Aurelio J
Xu, Hong
Changolkar, Lakshmi
Lee, Virginia M-Y
Lee, Edward B
Hong, Mei
Date Issued
September 2024
Journal
Journal of Biological Chemistry
Publisher
Elsevier BV
Version
Final published version
Abstract
Alzheimer's disease (AD) and many other neurodegenerative diseases are characterized by pathological aggregation of the protein tau. These tau aggregates spread in a stereotypical spatiotemporal pattern in the brain of each disease, suggesting that the misfolded tau can recruit soluble monomers to adopt the same pathological structure. To investigate whether recruited tau indeed adopts the same structure and properties as the original seed, here we template recombinant full-length 0N3R tau, 0N4R tau, and an equimolar mixture of the two using sarkosyl-insoluble tau extracted from AD brain and determine the structures of the resulting fibrils using cryoelectron microscopy. We show that these cell-free amplified tau fibrils adopt the same molecular structure as the AD paired-helical filament (PHF) tau but are unable to template additional monomers. Therefore, the PHF structure alone is insufficient for defining the pathological properties of AD tau, and other biochemical components such as tau posttranslational modifications, other proteins, polyanionic cofactors, and salt are required for the prion-like serial propagation of tauopathies.
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Creative Commons Attribution-NonCommercial-NoDerivatives
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DOI of Published Version
https://doi.org/10.1016/j.jbc.2024.107730
