Polymorphic structures of rapidly twisting 40-residue amyloid-β fibrils

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Amyloid-beta (Aβ) peptides form fibrils implicated in Alzheimer's disease.
• Aβ fibril structure is polymorphic and not fully understood, varying with growth conditions.
• Rapidly twisting Aβ40 fibrils present a distinct structural class.

Purpose of the Study:

• To characterize the high-resolution structures of rapidly twisting Aβ40 fibril polymorphs.
• To investigate the structural diversity within Aβ40 fibrils grown under uniform conditions.
• To compare in vitro-grown Aβ40 polymorphs with those found in brain tissue.

Main Methods:

• Cryogenic electron microscopy (cryo-EM) was employed for structural determination.
• Aβ40 peptides were grown under controlled conditions to isolate specific fibril types.
• Structural analysis focused on twist handedness, symmetry, molecular conformations, and intermolecular contacts.

Main Results:

• Three distinct rapidly twisting Aβ40 polymorphs were identified, all with similar cross-over distances (~25 nm).
• These polymorphs differed in twist handedness, symmetry, molecular conformations, and intermolecular contacts.
• Two polymorphs showed similarities to previously described Aβ40 polymorphs, including brain-derived ones, but with distinct conformational features.

Conclusions:

• Amyloid polymorphism is extensive, with multiple distinct structures arising even under identical growth conditions.
• Structural variations in Aβ40 fibrils include differences in molecular conformation and intermolecular packing.
• These findings enhance understanding of the relationship between in vitro and in vivo amyloid fibril structures.