Structural studies of mass- and ion mobility-selected Amyloid-β oligomers using cryogenic messenger-tagging infrared spectroscopy

• Applicant: Professor Dr. Kevin Pagel
• Subject Area: Analytical Chemistry ; Biophysics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567558930

This project aims to develop an innovative method for detecting and characterizing amyloid-beta (Aβ) oligomers, which are implicated in Alzheimer’s disease (AD) and known for their role in neurotoxicity and disease progression. These small, unstable protein aggregates are challenging to study due to their low abundance and structural diversity, and current analytical methods are limited in their ability to capture detailed structural information. To address these challenges, the project leverages a modified ion mobility-mass spectrometry (IM-MS) instrument that incorporates cryogenic messenger-tagging infrared (IR) spectroscopy, allowing for the high-resolution detection and structural analysis of individual Aβ oligomer states without requiring labels or chemical modifications. The project will focus on developing and refining this technology to capture the complex behavior and structural transitions of Aβ oligomers. This approach will be applied to analyze wild-type Aβ and engineered variants, mapping their structural dynamics as they assemble and differentiate. Additionally, the study will explore the effects of biologically relevant conditions - such as membrane-mimicking environments and the presence of metal ions - on the stability and structure of Aβ oligomers. By examining these factors, the project aims to uncover how different oligomeric states, and environmental interactions influence the aggregation pathways and potential toxicity of Aβ species. This research promises to yield new insights into the structural formation, dynamics, and interactions of Aβ oligomers. Findings could significantly enhance our understanding of AD mechanisms, laying a foundation for targeted interventions aimed at specific toxic Aβ forms and ultimately supporting the development of novel therapeutic strategies in Alzheimer's disease.

• DFG Programme: Research Grants
• Co-Investigator: Nicklas Österlund, Ph.D.