For decades, scientists have focused on amyloid plaques—abnormal clumps of misfolded proteins that accumulate between neurons—as a therapeutic target for Alzheimer’s disease. But anti-amyloid therapies haven’t made strong headway in treating the devastating condition. Now, researchers at Yale School of Medicine (YSM) are zeroing in on a byproduct of these plaques, called axonal spheroids, and exploring how to reverse their growth.
They published their findings March 10 in Nature Aging.
Axonal spheroids are bubble-like structures on axons—the part of the neuron that sends messages through electrical impulses—that form due to swelling induced by amyloid plaques. Previous research at YSM has shown that as these spheroids grow, they block electricity conduction in the axons, which can hinder the ability to communicate with other neurons.
In their latest study, this same team, led by Jaime Grutzendler, MD, Dr. Harry Zimmerman and Dr. Nicholas and Viola Spinelli Professor of Neurology and Neuroscience, and Yifei Cai, PhD, associate research scientist in neurology, used a novel approach to reveal the intricate molecular architecture of axonal spheroids. They also identified a potential target for reversing the axonal spheroid pathology.
And hopefully with that, we can improve neural function in the context of Alzheimer’s disease.
The team conducted their study in collaboration with Evangelia Petsalaki, PhD, of the European Molecular Biology Laboratory of the European Bioinformatics Institute and the YSM laboratories of Angus Nairn, PhD, Charles B.G. Murphy Professor of Psychiatry, and Kristen Brennand, PhD, Elizabeth Mears and House Jameson Professor of Psychiatry.
“Our research introduces a new hypothesis that axonal spheroids are a potentially very important pathological process,” says Grutzendler. “We believe that targeting these spheroids could be an important future avenue for treating Alzheimer’s disease by improving the overall electrical conduction and brain circuits—rather than just simply removing the amyloid plaques.”
In order for such a therapeutic to one day become a reality, researchers need a better understanding of how these structures form. “In this paper, we asked the question, ‘What is a spheroid?’” says Grutzendler. “In other words, what exactly are the mechanisms of spheroid formation?”
Blocking mTOR pathway reduces axonal spheroid size
For the study, the team investigated the proteins within axonal spheroids to identify the signaling pathways and protein-protein interactions that are occurring throughout their stages of growth. The team’s ultimate goal was to uncover underlying drivers of their formation that scientists could use as targets for halting the spheroids’ growth.
The researchers introduced antibodies that bind to a protein the team had previously found to accumulate throughout the axonal spheroids. They then used this protein as a hub from which they could tag all of the other proteins surrounding it. Think of it as akin to a network of sprinklers that together cover an entire lawn.
The researchers used this technique to tag and catalog all of the axonal spheroid proteins in both human and mouse postmortem brain tissue. They discovered hundreds of proteins that were not previously known to exist within the spheroids.
The approach also highlighted multiple important molecular signaling pathways within the structures. One of these, a pathway called mTOR that’s involved in cell growth and metabolism, was overactive in axonal spheroids. So, the team conducted an additional experiment in which they applied amyloid to neurons in a petri dish, causing them to develop structures similar to axonal spheroids in human and mouse tissue. When they introduced a pharmacological agent that blocked the mTOR pathway, the spheroids shrunk. This held true in mouse tissue as well.
Paving the way to new therapies for Alzheimer’s disease and beyond
Grutzendler hopes his team’s dataset will spur further research on axonal spheroids. These abnormal structures are not only significant in Alzheimer’s disease, but also other neurodegenerative diseases such as amyotrophic lateral sclerosis and Parkinson’s disease. Thus, future studies could lead to new therapeutic strategies for all of these conditions.
Grutzendler’s team also has plans to investigate other signaling pathways identified in the study to further understand how to prevent axonal spheroid formation.
“We’re moving in a more translational direction where we might be able to find very specific therapeutic approaches that will ameliorate the spheroid pathology,” he says. “And hopefully with that, we can improve neural function in the context of Alzheimer’s disease.”
The research reported in this news article was supported by the National Institutes of Health (awards RF1AG058257, R01NS115544, R01NS111961, R01AG068030, RF1AG065926, and R56AG071291). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by the Cure Alzheimer's Fund, the Yale/NIDA Neuroproteomics Center, the BrightFocus Foundation, the Yale Alzheimer's Disease Research Center, and the Alzheimer's Association.