Fibril structure of amyloid-β(1-42) by cryo-electron microscopy

Area of Science:

• Structural Biology
• Neuroscience
• Biochemistry

Background:

• Amyloid fibrils are protein aggregates implicated in neurodegenerative diseases.
• Amyloid-beta (Aβ) fibrils are the primary component of senile plaques in Alzheimer's disease (AD) brains.
• Understanding Aβ fibril structure is crucial for elucidating AD pathogenesis.

Purpose of the Study:

• To determine the high-resolution structure of an amyloid-beta (Aβ)(1-42) fibril.
• To elucidate the molecular architecture of Aβ fibrils and their subunit organization.
• To investigate the structural basis for fibril formation and potential implications for disease progression.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine fibril structure to 4.0-angstrom resolution.
• Solid-state nuclear magnetic resonance (ssNMR) experiments for complementary structural data.
• Detailed analysis of the electron density map to resolve backbone and side-chain details.

Main Results:

• The structure of an Aβ(1-42) fibril composed of two intertwined protofilaments was resolved.
• The backbone and most side chains, including the N terminus, were well-resolved, revealing an 'LS'-shaped subunit topology.
• The fibril ends exhibit distinct 'groove' and 'ridge' features, influencing binding pathways and fibril growth dynamics.

Conclusions:

• The determined fibril structure provides unprecedented atomic detail of Aβ aggregation.
• The 'LS'-shaped subunit and distinct fibril ends offer insights into the mechanism of fibril elongation.
• This structural information has significant implications for understanding Alzheimer's disease and developing targeted therapies.