What causes Alzheimer’s? Research in mice points to swelling on axons

Amyloids occur when a number of proteins connect together. When this happens, sometimes normal proteins begin to act abnormally. They lose their normal shape and “misfold” together, forming larger structures known as amyloid plaques.

Previous research has shown that amyloid plaques can occur anywhere in the body. Scientists have linked amyloid plaques moving to or occurring in the brain to dementia, including Alzheimer’s disease.

Using a mouse model, researchers found that each amyloid plaque in the brain causes swelling along any nearby axons — the very thin “cables” that run between the brain’s neurons.

Additionally, the formation of groups of lysosomes — organelles known for helping cells get rid of waste products — also leads to axonal swelling.

According to researchers, as the swelling on the axons increases, information is no longer able to move from one area of the brain to another, likely triggering dementia.

“Our study shows that the enlargement of the swellings is critical for causing electrical conduction blockages in axons,” Dr. Jaime Grutzendler, the Dr. Harry M. Zimmerman and Dr. Nicholas and Viola Spinelli professor of neurology and neuroscience at the Yale School of Medicine and senior author of the study, told Medical News Today.

He explained:

“Swellings in axons act as a capacitor — similar to electrical circuits — that acts as an electric current sink. This prevents the normal transmission of electrical signals through the axons, thereby disrupting communication with hundreds of other neurons.”

“Since each amyloid plaque is surrounded by hundreds of axons with swellings and each axon is connected to hundreds of other neurons and given that there are millions of amyloid plaques in the brain in Alzheimer’s, you can do the math and realize that there is a potential to disrupt billions of connections in the brain by these swelling mechanism,” Dr. Grutzendler added.

In the present study, the researchers also identified a potential new biomarker related to Alzheimer’s disease. PLD3 is a protein in lysosomes scientists say causes lysosomes to clump together along a neuron’s axon, bringing on swelling.

During the study, researchers used gene therapy to remove PLD3 from the neurons of mice with a condition similar to Alzheimer’s. They found removing PLD3 eased axon swelling and improved neuron function.

“We identified a molecule in lysosomes that when accumulated in excess makes these swellings get bigger,” Dr. Grutzendler told MNT.

“Importantly, when you reduce PLD3 with gene therapy the swellings are reduced and this leads to improvement of electrical conduction in axons as well as improvement in the communication between different neurons connected through those axons,” he noted.

The research team believes doctors can potentially use PLD3 as a biomarker to help diagnose Alzheimer’s risk, as well as provide a target for future therapies.

When asked about the next steps for this research, Dr. Grutzendler said they would be to continue doing rigorous studies to better understand how swellings form in the very beginning as soon as a tiny deposit of amyloid accumulates.

“Also important to understand how swellings affect electrical conduction,” he added. “More importantly, we will continue our studies [to understand] the various molecules that are involved in the initial formation and growth of wellings with the goal of finding therapeutic targets that could eventually be translated to humans.”

MNT also spoke with Dr. Jennifer Bramen, a senior research scientist at the Pacific Neuroscience Institute at Providence Saint John’s Health Center in Santa Monica, CA, who was not involved in this study.

She said that while neurodegeneration is the common reason why brain systems fail in Alzheimer’s disease, in this study the authors present support for a non-neurodegenerative process that might contribute to Alzheimer’s disease, which could be a target for therapy.

“One of the features of Alzheimer’s disease is impaired connections between brain regions,” Dr. Bramen explained. “Amyloid plaques are a hallmark of Alzheimer’s disease.”

“The authors describe one way that amyloid plaques might cause this disruption in electrical signals between brain regions. This is through the axonal swellings, which interrupt the flow of electricity in mice in their experiments.”

“As a researcher, I would like to see more work reproducing and building on these findings,” she added. “Most importantly, I would like to see research to support these findings in humans.”