Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) fibrils.
• Aβ42 is the more neurotoxic and critical form for AD etiology.
• Understanding Aβ fibril structure is key to developing AD therapies.

Purpose of the Study:

• To determine the atomic resolution structure of Aβ42 amyloid fibrils.
• To elucidate the molecular arrangement and interactions within Aβ42 fibrils.
• To provide a structural basis for designing Aβ42 aggregation inhibitors.

Main Methods:

• High-field magic angle spinning NMR spectroscopy.
• Collection of over 500 (13)C-(13)C, (13)C-(15)N distance and backbone angle constraints.
• Atomic resolution structure determination (PDB ID: 5KK3).

Main Results:

• Revealed a fibril core composed of a dimer of Aβ42 molecules.
• Each monomer adopts an S-shaped fold with four β-strands.
• Identified specific inter-monomer contacts (M35, L17, Q15) and parallel in-register arrangement.
• Outer surfaces are hydrophilic, while two hydrophobic cores are formed within the dimer.

Conclusions:

• The determined Aβ42 fibril structure offers insights into its aggregation mechanism.
• The structure facilitates the design of drugs targeting fibril surfaces to inhibit secondary nucleation.
• This work provides a foundation for novel therapeutic strategies against Aβ42 aggregation in Alzheimer's disease.