Cross-Seeding Controls Aβ Fibril Populations and Resulting Functions

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Amyloid peptides, like amyloid-beta (Aβ), aggregate into fibrils via primary and secondary nucleation.
• Fibril structural diversity (polymorphs) influences neurodegenerative effects.
• Understanding polymorph distribution is key to structure-function relationships and in vitro modeling.

Purpose of the Study:

• To investigate how cross-seeding wild-type (WT) Aβ1-40 with specific Aβ1-40 mutants (E22G, E22Δ) and WT Aβ1-42 affects fibril structural polymorph distribution.
• To determine the impact of altered structural distribution on fibril toxicity.

Main Methods:

• Cross-seeding experiments using WT Aβ1-40 with mutant Aβ1-40 and WT Aβ1-42.
• Transmission electron microscopy (TEM) to analyze fibril structures.
• Assessment of cytotoxicity profiles.

Main Results:

• Mutant Aβ1-40 fibril seeds transferred their structure to growing WT Aβ1-40 monomers during secondary nucleation.
• WT Aβ1-40 fibril seeds did not alter the structure of fibrils assembled from mutant Aβ1-40 monomers.
• Mutant fibril seeds imparted both structural characteristics and cytotoxicity to WT Aβ1-40 aggregates.

Conclusions:

• Mutant fibril seeds dictate the structural polymorph distribution and associated cytotoxicity of WT Aβ1-40 aggregates.
• Fibril structure and phenotype are linked at the polymorph population level.
• These properties are heritable through secondary nucleation to subsequent fibril generations.