Alzheimer in Super-Resolution

Brain showing hallmarks of Alzheimer's disease, plaques in blue. (Source: Zeiss)

Brain showing hallmarks of Alzheimer’s disease, plaques in blue. (Source: Zeiss)

A new super-resolution imaging technique allows researchers to track how surface changes in proteins are related to neuro­degenerative diseases such as Alzheimer’s and Par­kinson’s diseases. Researchers have developed a new imaging technique that makes it possible to study why proteins associated with Alzheimer’s and Parkinson’s diseases may go from harmless to toxic. The technique uses multi-dimen­sional super-resolution imaging that makes it possible to observe changes in the surfaces of individual protein molecules as they clump together. The tool may allow researchers to pinpoint how proteins misfold and even­tually become toxic to nerve cells in the brain, which could aid in the development of treatments for these deva­stating diseases.

The researchers, from the University of Cambridge, have studied how hydro­phobicity in the proteins amyloid-beta and alpha synuclein – which are associated with Alzheimer’s and Parkinson’s respectively – changes as they stick together. It had been hypo­thesised that there was a link between the hydro­phobicity and toxicity of these proteins, but this is the first time it has been possible to image hydro­phobicity at such high resolution. “These proteins start out in a relatively harmless form, but when they clump together, something important changes,” said Steven Lee from Cambridge’s Department of Chemistry. “But using con­ventional imaging techniques, it hasn’t been possible to see what’s going on at the molecular level.”

In neuro­degenerative diseases such as Alzheimer’s and Parkinson’s, naturally-occurring proteins fold into the wrong shape and clump together into filament-like structures known as amyloid fibrils and smaller, highly toxic clusters known as oligomers which are thought to damage or kill neurons, however the exact mechanism remains unknown. For the past two decades, researchers have been attempting to develop treatments which stop the pro­liferation of these clusters in the brain, but before any such treatment can be developed, there first needs to be a precise under­standing of how oligomers form and why.

“There’s something special about oligomers, and we want to know what it is,” said Lee. “We’ve developed new tools that will help us answer these questions.” When using conven­tional micro­scopy techniques, physics makes it impossible to zoom in past a certain point. Essen­tially, there is an innate blur­riness to light, so anything below a certain size will appear as a blurry blob when viewed through an optical micro­scope, simply because light waves spread when they are focused on such a tiny spot. Amyloid fibrils and oligomers are smaller than this limit so it’s very difficult to directly visualise what is going on.

However, new super-reso­lution techniques, which are 10 to 20 times better than optical microscopes, have allowed researchers to get around these limitations and view biological and chemical processes at the nano­scale. Lee and his colleagues have taken super-resolution techniques one step further, and are now able to not only determine the location of a molecule, but also the environ­mental properties of single molecules simul­taneously.

Using their technique, known as sPAINT (spectrally-resolved points accumulation for imaging in nanoscale topo­graphy), the researchers used a dye molecule to map the hydro­phobicity of amyloid fibrils and oligomers implicated in neuro­degenerative diseases. The sPAINT technique is easy to implement, only requiring the addition of a single trans­mission diffraction gradient onto a super-reso­lution micro­scope. According to the researchers, the ability to map hydro­phobicity at the nano­scale could be used to understand other bio­logical processes in future. (Source: U Cambridge)

Reference: M. N. Bongiovanni et al.: Multi-dimensional super-resolution imaging enables surface hydrophobicity mapping, Nat. Comms. (2016). DOI: 10.1038/ncomms13544

Link: The Vendruscolo Laboratory, University of Cambridge, UK

Speak Your Mind

*