The structure of amyloid beta (Aβ) fibrils isolated from the brain tissue of patients with Alzheimer’s disease has been shown to differ from laboratory-derived fibrils.

The research, published in Nature Communications, found brain-derived Aβ fibrils had a right-hand twisted structure – strikingly different from the left-hand twist seen in lab-derived fibrils.

As well, cryo-electron microscopy of fibril morphology found the characteristic peptide fold in brain-derived fibrils was distinctly different to that of the in-vitro fibrils

The limbic asked co-author Dr Jay Rasmussen, a post-doctoral researcher at the Queensland Brain Institute, about the study and its implications.

Why have we relied on knowledge of the structure of in-vitro generated Aβ fibrils to date? And why would they be so different from patient-derived fibrils?

Working with in vitro made amyloid fibrils is much easier than a brain sample, as one can produce a pure sample that is full of homogeneous fibrils in vitro. This sample is then better suited for structural analysis, which often employs averaging across multiple fibrils to produce a high-resolution structure. The technical feat in this study was the purification of high-quality amyloid fibrils from the brain and using cryo-EM to look at individual fibrils. You can probably imagine that the defined environment for making in vitro fibrils is quite different from the brain’s complex tissue environment and this is likely the reason for the differences we identified.

You found that the fibrils, irrespective of their source, are largely polymorphic. But are there enough conserved morphological features in the patient-derived fibrils to provide clues to the structural basis of Alzheimer’s disease?

This question largely comes down to the level of detail being considered when looking at a fibril structure. I think our critical finding was not only that polymorphisms exist but also that there is a conserved ultrastructural right-handed twist in patient-derived fibrils. Additionally, the protofilaments that make up an amyloid fibril were similar between patient samples. We have identified these key features of Alzheimer’s disease samples, which may be telling us something larger about amyloid fibril growth in the brain during disease.

The study suggests that targeting specific fibril morphologies with appropriately selective inhibitors may interfere with the disease process. How do you see this research moving forward? What do we need to know next?

In general, I think we need to investigate more about the heterogeneity in fibril structures between patients and subtypes of Alzheimer’s disease. Additionally, our study focused on vascular amyloid as opposed to parenchymal plaques and it will be very interesting to determine how the structure of these two different types of amyloid deposit compare. Another critical next step, is defining how different fibril structures correlate to disease characteristics and progression. With this knowledge, we will be able to determine conclusively how fibril structure influences disease and design potent inhibitors to stop Alzheimer’s disease.