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Brain-seeded 42-residue amyloid-β fibrils that resemble fibrils directly extracted from Alzheimer’s disease brain tissue
Journal article   Peer reviewed

Brain-seeded 42-residue amyloid-β fibrils that resemble fibrils directly extracted from Alzheimer’s disease brain tissue

Kent R. Thurber, Myungwoon Lee and Robert Tycko
Journal of molecular biology, Forthcoming
10 Aug 2026
DOI: https://doi.org/10.1016/j.jmb.2026.169983
PMID: 42575163
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Abstract

Alzheimer’sdisease Amyloid-β cryogenicelectronmicroscopy fibrilstructure moleculardynamics polymorphism
[Display omitted] •Structures of two new Aβ42 fibril polymorphs are determined by cryo-EM methods.•These fibrils were derived from cortical tissue of an AD patient by seeded growth.•Similarities to structures of directly-extracted Aβ42 fibrils are found.•MD simulations reveal interactions that stabilize distinct polymorphs. Fibrils formed by the 42-residue amyloid-β peptide (Aβ42) are known to be polymorphic, with molecular conformations and supramolecular structures that depend on conditions of nucleation, growth, seeding, or other factors. Structural studies of Aβ42 fibrils that develop in human brain tissue have been based on two different approaches, either direct extraction and partial purification of fibrils from brain tissue for characterization by cryogenic electron microscopy (cryo-EM) or growth of fibrils in vitro from seeds in amyloid-containing brain tissue extracts for characterization by solid state nuclear magnetic resonance (ssNMR) or cryo-EM. To date, studies of brain-extracted and brain-seeded Aβ42 fibrils have produced qualitatively different sets of structures. Here we report structures of two new brain-seeded Aβ42 fibril polymorphs, derived from cortical tissue of an Alzheimer’s disease (AD) patient, that share certain structural features with previously characterized polymorphs extracted from AD brain tissue. These structures contribute to our understanding of the relationships between brain-seeded and brain-extracted fibril structures and expand our understanding of the full range of polymorphism in amyloid-β fibrils.

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