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Novel imaging approach open doors to understanding key pathological processes inside neurons

Profile photo of Oxana Klementieva.
Photo: Agata Garpenlind

A combination of two imaging methods can be used to achieve structural and chemical information within a single neuron. Researchers from MultiPark at Lund University recently developed this approach. Their study reveals that amyloid aggregates, implicated in Alzheimer’s disease, may cause clustering of iron in primary neurons.

Alzheimer's disease is a major cause of dementia. Understanding where and how the first pathological changes begin could open doors towards developing preventative therapies for the disease. Much research focuses on unraveling molecular mechanisms of the disease to find effective treatments. As previous research indicates that accumulation of misfolded amyloid-β seems to start inside the neurons, being able to visually observe this process within the cells becomes crucial. And for this, researchers from the Medical Microspectroscopy group used a new approach, taking advantage of the combination of two already existing techniques.

“With our approach, we can capture elemental distribution and fibrillary forms of amyloid-β proteins within the same neuron at sub-cellular resolution”, explains Oxana Klementieva, leading the Medical Microspectroscopy group at MultiPark and last author of the study.

The secret of getting this detailed structural information is to combine already available techniques that stand at the opposite ends of the electromagnetic spectrum. Together, they are a perfect match, complementing each other. Specifically, using hard X-rays, metal ions can be traced with the range of nanometers, while using the infrared part of the spectrum, it is possible to assess molecular structures. Thus, using correlative optical photothermal infrared and X-ray fluorescence for chemical imaging, it is possible to trace elements and relevant molecular structures directly in neurons.

Hopefully, our proof of concept study could motivate other researchers at the Medical Faculty to use the synchrotron-based imaging tools available at MAXIV.

“We believe that our methods can be useful to shed light on molecular mechanisms of AD,” continues Oxana Klementieva.

In collaboration with Experimental Dementia Research, led by Gunnar Gouras, they investigated the amyloid structure in primary neurons.

“Our experiments show that clusters of iron can co-localize with elevated amyloid β-sheet structures and oxidized lipids. This has never been shown before at subcellular resolution,” tells Nadja Gustavsson, a Ph.D. student in the Medical Microspectroscopy group and the first author of the study.

To better understand the mechanisms of β‐amyloid aggregation, the approach has to be further developed. One opportunity is to use it together with immunofluorescent microscopy. Such multimodal imaging may provide a more thorough analysis of structural changes of specific proteins in different compartments of the cell. For example, synapses or vesicles, like endosomes and lysosomes, can be studied in greater detail.

“Hopefully, our proof of concept study could motivate other researchers at the Medical Faculty to use the synchrotron-based imaging tools available at MAXIV,” concludes Oxana Klementieva.

This work was published in Light: Science & Applications in July 2021. 

Read the article. 

This work was supported by the Swedish Research Council Starting Grant, Vinnova, Grafoord, Swedish Brain Foundation, Royal Physiographic Society of Lund; Åke Wiberg Stiftelse.