Biophysical investigation of the mechanisms behind pore-formation by amyloid-β peptides in biomembranes

The amyloid-β (Aβ) peptide spontanously self-assembles into various aggregates with neurotoxic properties.

Our aim is to characterize the early aggregation events, and how they are modulated by other molecules of cellular or therapeutic interest. Particularly the interaction with membrane environments. Oligomers will be enriched, isolated and studied in vitro by biophysical techniques.

Novel native ion mobility-mass spectrometry techniques will primarily be used, but also optical spectroscopy and imaging techniques.The purpose is to better pinpoint the molecular mechanisms relevant to neurodegeneration in Alzheimer’s disease (AD).

Formation of fibrilar Aβ aggregates has so far failed as a target for AD treatment, suggesting a different underlying mechanism for Aβ toxicity.

One alternative mechanism is pore-formation in biomembranes by pre-fibrilar Aβ oligomers, which results in uncontrolled cell leakage. The underlying biophysical and biochemical properties of such pore-formation need to be determined.

We will present novel ways to monitor formation of Aβ oligomers in membrane environments and how the process is modulated by molecular enhancers and inhibitor.

This will give new and unique mechanistic insights into pre-fibrillar Aβ aggregation.This 4-year project will be led by Ilag in collaboration with Landreh (native MS expert) and Gräslund (amyloid biophysics expert), and will involve 2 Ph.D. students.