Researchers from UNSW Sydney and the Tata Institute of Fundamental Research in India shed new light on how amyloid beta – a peptide associated with Alzheimer’s disease – kills nerve cells.

By creating different variations of amyloid beta, the researchers teased apart the functions of different segments of the peptide. They discovered that one part of the peptide facilitates entry into neuronal cells, while the other was needed to initiate the cell death program.

Their findings are published in the journal ACS Chemical Neuroscience.

Like many proteins, amyloid beta has both ordered and disordered regions. Ordered protein regions form stable 3-dimensional structures, while disordered regions can form distinct structures under different circumstances– for example, when they clump together, or when they interact with membranes. And these structural changes can change the way proteins behave.

“That’s why understanding the disordered domain is important,” says Dr Senthil Arumugam of UNSW Medicine’s Single Molecule Science, who co-led the study with Professor Sudipta Maiti of the Tata Institute of Fundamental Research.

Using the lattice light sheet microscope developed at UNSW Sydney, the researchers could track the different variants of amyloid beta inside cells and moving in intracellular compartments called endosomes. Inside the endosomes, they mostly found amyloid beta forms that were missing the disordered regions. And without the disordered segment, the peptide could not induce cell death in neurons.

“We need rapid imaging because endosomes move around very quickly, and they all move randomly in 3-D space,” says Senthil.

“With lattice light sheet microscopy, you’re imaging an entire cell. You can count the absolute number of endosomes, see how many of them have amyloid beta inside, and see how the different variants move around. The motility characteristics all provide clues to the mechanisms of amyloid beta toxicity.”

[Image: Tracking the motility of amyloid beta (red) and endosomes (grey) inside a neuron. Their trajectories are measured and quantified with high speed and super-resolution using lattice light sheet microscopy.]