Strain-specific Fibril Propagation by an Aβ Dodecamer

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Low molecular weight amyloid-β (Aβ) oligomers are key toxic agents in Alzheimer disease (AD) pathogenesis.
• Microstructural differences in Aβ oligomers lead to fibril polymorphism and correlate with AD diversity.
• Conformational strains of Aβ oligomers may significantly influence AD phenotypic outcomes.

Purpose of the Study:

• To investigate the strain-specific propagation of amyloid-β (Aβ) oligomers.
• To determine if Aβ oligomeric strains can faithfully propagate their structure.
• To elucidate the mechanism of Aβ oligomer strain propagation.

Main Methods:

• Utilized transgenic CRND8 mice for in vivo studies.
• Investigated in vitro fibril propagation of a specific Aβ42 dodecamer (LFAOs).
• Analyzed fibril morphology and regeneration through sonication.

Main Results:

• Demonstrated fibril propagation of the large fatty acid-derived oligomer (LFAO) Aβ42 strain.
• Showed that LFAOs selectively induce acute cerebral amyloid angiopathy (CAA) in mice.
• Characterized in vitro propagation as a three-step process involving LFAO unit association.
• Observed that LFAO-seeded fibrils have a distinct morphology composed of repeating LFAO units, regenerable by sonication.

Conclusions:

• Established a mechanistic perspective on the strain-specific propagation of Aβ oligomers.
• Highlighted the role of LFAO oligomeric strain in inducing CAA.
• Provided evidence for the faithful propagation of Aβ oligomer structure, impacting AD pathogenesis.