Molecular structure of a prevalent amyloid-[beta] fibril polymorph from Alzheimer's disease brain tissue

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Date: Jan. 26, 2021
Publisher: National Academy of Sciences
Document Type: Report
Length: 6,879 words
Lexile Measure: 1510L

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Abstract :

Amyloid-[beta] (A[beta]) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer's disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue A[beta] peptides (A[beta]40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solidstate NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived A[beta]40 fibril polymorph from typical AD patients. The structure, which has 2.8-A resolution according to standard criteria, differs qualitatively from all previously described A[beta] fibril structures, both in its molecular conformations and its organization of cross-[beta] subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three A[beta]40 molecules per 4.8-A [beta]-sheet spacing, a fourlayered architecture, and fully extended conformations for molecules in the central two cross-[beta] layers. The cryoEM density, ssNMR data, and MPL data are consistent with [beta]-hairpin conformations for molecules in the outer cross-[beta] layers. Knowledge of this brainderived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility. amyloid structure | Alzheimer's disease | cryo-electron microscopy | solid-state NMR

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Gale Document Number: GALE|A649927430