Groundbreaking research shows that sugar is critical to the prevention and treatment of Alzheimer’s disease.

Researchers say they have found that a particular sugar molecule may play a key role in the development of Alzheimer’s disease. (CREDIT: Creative Commons)

Researchers at Johns Hopkins University said in a small “reverse engineered” study using the brain tissue of five people who died of Alzheimer’s disease, they found 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 serve as a new target for early diagnostic tests, treatment, and possibly prevention of Alzheimer’s disease, the researchers say.

The study was published in Journal of Biological Chemistry.

Alzheimer’s disease is the most common form of dementia in the United States. Approximately 5.8 million Americans affected., a progressive disease occurs when nerve cells in the brain die due to a buildup of harmful forms of proteins called amyloid and tau.

Clearing out disease-causing forms of amyloid and tau is the job of brain immune cells called microglia. Earlier studies have shown that when cleaning is disrupted, Alzheimer’s is more likely to develop. In some people, this is caused by an excess of a receptor on microglial cells called CD33.

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“The receptors are not active on their own. There must be something to them to stop microglia from clearing these toxic proteins in the brain, says Ronald Schnaar, Ph.D., John Jacob Abel Professor of Pharmacology at Johns Hopkins University School of Medicine and director of the lab that led the study.

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

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

The CD33/Siglec-8 ligand of the human brain is distributed throughout the parenchyma of the cerebral cortex. (CREDIT: Journal of Biological Chemistry)

To identify this enigmatic glycoprotein, the researchers first needed to separate it from other brain glycoproteins. Since it was the only one in the brain that attached to CD33, they used this feature to “catch” it and detach it.

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

The same RPTPζ glycoform carries both CD33 and Siglec-8 ligands. A, Equal aliquots of human cerebral cortex total protein extract from four donors (numbered) were separated on replicate agarose-acrylamide composite gels and loaded onto PVDF. (CREDIT: Journal of Biological Chemistry)

The researchers then determined the identity of the protein component by taking its “fingerprint” 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 was able to conclude 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.

The group had previously found the same glycan “signature” on a protein that controls allergic reactions in the respiratory tract, and that disruption of the glycan attenuated allergic reactions in mice.

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

Further experiments showed that in the brain tissue of five people who died from Alzheimer’s disease, there was more than twice as much RPTP zeta S3L as in donors who did not have this disease. This means that this glycoprotein can bind to more CD33 receptors than a healthy brain, limiting the brain’s ability to clear harmful proteins.

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

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

Other researchers involved in this study include Ryan Porell, Steve Fernandez, Eila Maenpaa, T. August Lee, Tong Lee, Philip Wong, Zaikuan Yu, Benjamin Orsburn, and Namanje Bumpus of the Johns Hopkins University School of Medicine; Kazuhiro Aoki and Michael Thiemeyer of the University of Georgia and Russell Mathew of the State University of New York, Upstate Medical University.

For more science news, visit our New Discoveries section at The bright side of the news.

Note: Materials provided above by Johns Hopkins Medicine. Content can be edited for style and length.

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