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May 27, 2022
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A specific sugar molecule may play a key role in the development of Alzheimer’s disease

A specific sugar molecule may play a key role in the development of Alzheimer's disease

Researchers at Johns Hopkins Medical Center claim that by “reverse-engineering” the brain tissue of five people who died of Alzheimer’s disease, they discovered that a particular sugar molecule may play a key role in the development of Alzheimer’s disease. If further research confirms this finding, the molecule known as glycan could be a new target for early diagnosis, treatment, and possibly prevention of Alzheimer’s disease, the researchers say.

The study was published online April 20 in the Journal of Biological Chemistry. Alzheimer’s disease is the most common form of dementia in the US. The progressive disease, which affects about 5.8 million Americans, occurs when nerve cells in the brain die due to a buildup of harmful forms of proteins called amyloid and tau.

Clearing the brain of pathogenic forms of amyloid and tau is the job of brain immune cells called microglia. Earlier studies have shown that Alzheimer’s disease is more likely to occur when the cleansing process is disturbed. In some people, this is caused by an overabundance of a receptor on microglial cells called CD33.

“The receptors are not active on their own. Something has to be connected to them to block the microglia from clearing the brain of these toxic proteins,” says Ronald Schnaar, Ph.D., John Jacob Abel Professor of Pharmacology at Johns Hopkins University School of Medicine and director of the laboratory. who led the study.

Past research by scientists has shown that for CD33, these “junction” molecules are specific sugars. Known to scientists as glycans, these molecules are carried around the cell by specialized proteins that help them find the appropriate receptors. The combination of a protein and a glycan is called a glycoprotein.

To find out which glycoprotein is associated with CD33, Schnaar’s research team obtained brain tissue from five people who died of Alzheimer’s disease and five people who died of other causes from the Johns Hopkins Alzheimer’s Research Center. Among the many thousands of glycoproteins they collected from brain tissue, only one was associated with CD33.

To identify this enigmatic glycoprotein, the researchers first had to separate it from other brain glycoproteins. Since only this glycoprotein in the brain was associated with CD33, they used this feature to “catch” it and separate it.

Glycans are made up of various sugar building blocks that influence molecular interactions. Such sugars can be identified by their constituents. The researchers used chemical tools to deconstruct the glycan step by step, establishing the identity and order of its building blocks. The researchers identified the glycan component of the glycoprotein as sialylated keratan sulfate.

The researchers then determined the identity of the protein component by fingerprinting it using mass spectroscopy, which identifies the building blocks of the protein. By comparing the molecular composition of the protein with a database of known protein structures, the research team concluded that the protein portion of the glycoprotein is receptor tyrosine phosphatase (RPTP) zeta.

The researchers named the combined structure of the RPTP glycoprotein zeta S3L. Previously, the team had found the same glycan “signature” on a protein that controls allergic reactions in the respiratory tract, and disruption of the glycans muted allergic reactions in mice.

“We suspect that the glycan contained in RPTP zeta may play a similar role in microglia deactivation via CD33,” says Anabel González-Gil Alvarenga, Ph.D., a postdoctoral fellow in Schnaar’s lab and first author of the study.

Further experiments showed that the brain tissue of five people who died of Alzheimer’s disease had more than twice as much RPTP zeta S3L as that of non-AD donors. This suggests that this glycoprotein may bind to more CD33 receptors than in the healthy brain, limiting the brain’s ability to clear harmful proteins.

“The identification of this unique glycoprotein is a step towards finding new drug targets and potentially early diagnosis of Alzheimer’s disease,” says Gonzalez-Gil.

Next, the researchers plan to further study the structure of RPTP zeta S3L to determine how the glycans attached to it give the glycoprotein its unique ability to interact with CD33.

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