To Understand Alzheimer’s Disease, Researchers Turn to Myelin Sheath

The disruption of axons—the thread-like part of nerve cells that transmits electrical signals—is associated with Alzheimer’s disease. One way axonal function may be hindered is through damage to the myelin sheath, a fatty coating that wraps around axons. Similar to the plastic or rubber used to insulate a cable, the myelin sheath allows neurons to quickly communicate with each other. When the structure is impaired, so is the conduction of electrical signals.

To better understand any pathological processes related to Alzheimer’s disease that might affect the myelin sheath, Yale researchers analyzed proteins in human brain tissue, focusing on the sub-compartment that lies between an axon and its myelin sheath.

They found proteins in this sub-compartment that differed between people who did and did not have Alzheimer’s disease and discovered structural abnormalities at the myelin-axon interface that may hinder electrical signaling. The team published their findings June 13 in Nature Neuroscience.

“If we learn how the proteins that make up the myelin sheath are affected in the diseased state compared to a non-diseased state, we might be able to figure out what’s going on when the disease develops,” says Jaime Grutzendler, MD, Dr. Harry M. Zimmerman and Dr. Nicholas and Viola Spinelli Professor of Neurology and Neuroscience at Yale School of Medicine (YSM) and the study’s principal investigator.

Different cell types are impacted by Alzheimer’s disease in different ways, and oligodendrocytes are especially vulnerable to the disease. These cells produce the myelin that wraps around and protects axons. This is one of the reasons the myelin sheath is an intriguing area to investigate.

Grutzendler’s team, including first author Yifei Cai, PhD, a research scientist who spearheaded these studies, used a technique that tagged all of the proteins within their area of interest with a special antibody. That allowed the researchers to isolate the proteins and then identify them using mass spectrometry. “This approach allows us to look at the specific proteins that are contained within the very, very narrow space of the myelin sheath,” Grutzendler says.

Their analyses revealed protein differences between tissue affected by Alzheimer’s disease and that of healthy individuals. Some of these differences were related to the formation of amyloid—abnormal protein aggregates that can accumulate in tissues and are linked to Alzheimer’s disease—axon growth, and lipid metabolism.

“Myelin requires a lot of lipids [a group of molecules that includes fats] for normal function,” Grutzendler says. “In Alzheimer’s disease, lipid metabolism could be abnormally affected in a way that alters the normal function of myelin.”

The team also used a super-resolution imaging technique called expansion microscopy to further analyze brain tissue samples. Interestingly, they found that the amount of myelin in tissues affected by Alzheimer’s disease did not significantly differ from age-matched healthy controls. “It seems that the total amount of the myelin in the myelin sheaths is relatively preserved,” says Grutzendler.

Nerves are coated in myelin, but have tiny gaps called “nodes of Ranvier” where the nerve is exposed to boost signals. Right next to these gaps are “paranodes,” where the myelin sticks tightly to the nerve, helping anchor it in place and organize the nerve for fast, accurate signaling.

While they did not find differences in the amount of myelin, the team did find changes in the proteins at these paranodes. These changes could affect how well the nerve signals travel.

Paranodes are also important because they contain channels that help transfer nutrients between the myelin and the nerve, as well as clear waste. The team discovered that amyloid can build up in unique spiral-shaped loops around the axons, often forming near the paranodes. “These channels are clogged up by the accumulation of these amyloid proteins,” says Grutzendler. “As a result of that, we think this is affecting the function of the axon and myelin together.”

In some cases, the researchers observed swelling of the axon near these amyloid loops. “It’s possible that this amyloid accumulation around the axon causes constriction of the paranode channels and leads to swelling,” says Grutzendler. “It’s almost like tying a knot around a straw—if you constrict it and keep blowing into it, you’ll see an enlargement of the straw by the knot.”

There were also abnormal patterns of myelin around axonal spheroids—bubble-like structures on axons that form due to the swelling. “This can have important implications because not only is the spheroid affecting electrical conduction, but also the different degrees of myelination of the spheroids on top of that,” says Grutzendler. “It’s a double whammy.”

In future studies, Grutzendler’s team hopes to use these protein data to see if they can improve some of the abnormalities they found at the myelin-axon interface.

“We are still at the hypothesis-generating phase,” Grutzendler says. “We have a lot more work to do in the future.”

Co-authors of the study are Fuyi Chen, Tram Huynh, Jean Kanyo, Peiyang Tang, Lukas Fuentes, Amber Braker, Rachel Welch, Anita Huttner, Lei Tong, Peng Yuan, TuKiet Lam, and Angus Nairn of Yale; Iguaracy Pinheiro-de-Sousa and Evangelia Petsalaki of the European Bioinformatics Institute; and Mykhaylo Slobodyanyuk and Jüri Reimand of the Ontario Institute for Cancer Research.

The research reported in this news article was supported by the National Institutes of Health (awards RF1AG058257, R01NS115544, and R01NS111961) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The study was also supported by the Cure Alzheimer's Fund, a Yale/NIDA Neuroproteomics Center Pilot Project Grant, the BrightFocus Foundation, the Yale Alzheimer’s Disease Research Center, the Alzheimer’s Association, and the EMBL Corporate Partnership Programme.