Heterotypic Amyloid β interactions facilitate amyloid assembly and modify amyloid structure

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Pathological amyloid deposition in specific brain regions and cell susceptibility remain poorly understood.
• Amyloid deposition is driven by the self-assembly of aggregation-prone regions (APRs) that form cross-β structures.

Purpose of the Study:

• To investigate if heterotypic interactions between Aβ APRs and homologous segments in other human proteins can modify Aβ amyloid assembly.
• To explore the role of these interactions in Alzheimer's disease (AD) pathogenesis.

Main Methods:

• Mining proteomics data of Aβ plaques from AD patients to identify enriched proteins with sequences homologous to Aβ APRs.
• In vitro studies to assess the impact of identified homologous APRs on Aβ assembly kinetics, fibril morphology, and deposition patterns.
• Transient expression of identified proteins in an Aβ reporter cell line to observe their effect on Aβ aggregation.

Main Results:

• Proteomics data revealed an enrichment of proteins with sequences homologous to Aβ APRs in human AD plaques.
• Identified homologous APRs modified Aβ assembly kinetics, fibril morphology, and deposition patterns in vitro.
• Transient expression of three identified proteins promoted Aβ amyloid aggregation in a reporter cell line.
• No bias towards heterotypic interactions was observed in AD mouse models.

Conclusions:

• Heterotypic APR interactions may play a significant, previously unrecognized role in amyloid deposition diseases like AD.
• These interactions could influence the initiation and progression of amyloid pathology.
• Further research is warranted to elucidate the precise mechanisms and therapeutic potential of targeting heterotypic interactions.