Advanced Imaging Captures Protein Clumps in Neurons at Early Alzheimer Stages

Advanced Imaging Captures Protein Clumps in Neurons at Early Alzheimer Stages
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Scientists used a new imaging technique to assess the structure of amyloid-beta aggregates — known culprits in Alzheimer’s development — that are present inside nerve cells at early stages of the disease, a study reports.

These findings, from a mouse model, may be important to understanding the different stages of Alzheimer’s progression.

The study, “Super‐Resolution Infrared Imaging of Polymorphic Amyloid Aggregates Directly in Neurons,” was published in the journal Advanced Science.

During the development of Alzheimer’s, a protein called amyloid-beta clumps and forms aggregates inside nerve cells (neurons). Over time, these aggregates become plaques that accumulate between nerve cells and disrupt their communication. These amyloid-beta plaques are toxic to nerve cells, and as the disease progresses, they cause nerve cells to die.

However, these plaques only become visible in brain tissue when the disease is already in an advanced stage. 

Researchers previously used a mouse model of Alzheimer’s to show that the structure of beta-amyloid-beta itself was altered early in the disease, before the formation of amyloid-beta plaques.

It is not yet fully understood what happens inside nerve cells before amyloid-beta plaques appear, and why they cause nerve cells to die.

“This is a question that researchers have long struggled to find answers to. We have not had enough imaging techniques to study the structural changes in nerve cells,” Oxana Klementieva, the study’s lead author and group leader for medical microscopy at Lund University, in Sweden, said in a press release.

New techniques are “required to detect very early changes, and therefore potentially understand the triggers,” Klementieva added.

Until now, techniques used to study amyloid-beta in nerve cells required chemical processing of the cells, which could affect the structure of amyloid-beta aggregates. A recently developed method, called optical photothermal infrared (O‐PTIR),  does not require this chemical processing. 

“The reason why we do not yet have effective treatments for Alzheimer’s disease have to do with the complexity of the brain,” said Gunnar Gouras, a professor of experimental neurology at Lund who also participated in the study.

Gouras believes that technology shifts like this method are essential to understanding disorders like Alzheimer’s. 

Scientists at Lund University and Synchrotron SOLEIL, in France, used O‐PTIR to study amyloid-beta aggregation directly inside nerve cells of a mouse model of Alzheimer’s.

Images were obtained during early disease stages, before nerve cell death is thought to occur.

Differing structures of amyloid-beta aggregates were found in different areas of a given nerve cell, suggesting that different mechanisms of this protein’s aggregation exist at the same time in one single neuron.

“We saw that the structure of the protein changes in different ways depending on where in the nerve cell it is. So far, there have been no methods that can produce these types of images, giving us insight into what the first molecular changes in neurons actually look like in Alzheimer’s disease,” Klementieva said.

The researchers suggest that the structural changes observed in amyloid-beta aggregates inside neurons could play a role in disease progression, since “different neurotoxic mechanisms might be prevalent at different stages of AD [Alzheimer’s disease],” leading to differences in disease progression.

“If [amyloid-beta aggregation] depends on several different mechanisms, something I believe to be the case, we therefore, would need different types of treatments,” Klementieva said.

Researchers suggest that future work investigate if the same changes in amyloid-beta structure can be detected in other animal models, as well as nerve cells from patients. “If replicated, then following the structural changes could be used as a method to screen drugs to prevent amyloid formation at the neuronal level,” the researchers wrote.

The new technology may also be useful in study of protein structures related to other disorders that affect the brain, like Parkinson’s disease, Lewy Body dementia and frontal lobe dementia.

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