Medical researchers Johns Hopkins associate sugar-saturated protein with Alzheimer's disease

Medical researchers Johns Hopkins associate sugar-saturated protein with Alzheimer’s disease

The study was published online on April 20 in the Journal of Biological Chemistry.

Alzheimer’s disease is the most common form of dementia in the United States. It affects an estimated 5.8 million Americans, and progressive disorder occurs when nerve cells in the brain die as a result of an accumulation of harmful forms of proteins called amyloid and tau.

Purification of pathogenic forms of amyloid and tau is the job of immune cells in the brain, called microglia. Previous studies have found that Alzheimer’s disease is more likely to occur when cleaning is disrupted. In some people, this is due to an excess of a receptor on the cells of the microglia called CD33.

“Receptors are not active on their own.” Something must be connected to them to prevent microglia from clearing these toxic proteins in the brain, says Ronald Schnaar, Ph.D., professor of pharmacology John Jacob Abel of Johns Hopkins University School of Medicine and director of the laboratory that led the study.

Past studies by scientists have shown that these “linker” molecules are special sugars for CD33. These molecules, known to scientists as glycans, are transported around the cell using specialized proteins that help them find their suitable receptors. The protein-glycan combination is called a glycoprotein.

In an effort to determine which specific glycoprotein is associated with CD33, Schnaar’s research team obtained brain tissue from five people who died of Alzheimer’s disease and from five people who died of other causes from the Johns Hopkins Alzheimer’s Disease Research Center. Of the many thousands of glycoproteins that collected from brain tissues, only one was attached to CD33.

To identify this mysterious glycoprotein, researchers first had to separate it from other brain glycoproteins. Because it was the only one in the brain that joined CD33, they used this feature to “catch” and separate it.

Glycans are made up of various sugar building blocks that affect the interactions of molecules. Such sugars can be identified by their components. The researchers used chemical tools to deconstruct the glycan step by step, determining the identity and order of its building blocks. The researchers identified the glycan portion of the glycoprotein as sialylated keratan sulfate.

The researchers then determined the identity of the protein component by taking its “fingerprint” using mass spectroscopy, which identifies the protein building blocks. 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 was zeta receptor tyrosine phosphatase (RPTP).

The researchers named the combined glycoprotein structure RPTP zeta S3L.

The group has previously found the same glycan “signature” on a protein that controls allergic reactions in the airways and that glycan disruption suppresses allergic reactions in mice.

“We suspect that the glycan signature carried on the RPTP zeta may have a similar role in inactivating microglia through CD33,” said Anabel Gonzalez-Gil Alvarenga, Ph.D., a postdoctoral fellow at Schnaar and the 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 donors who did not have the disease. This means that this glycoprotein can bind to more CD33 receptors than a healthy brain, which limits the brain’s ability to purify harmful proteins.

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

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

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

This research was supported by the National Institute on Aging (AG062342 and AG068089), the National Institute of the Heart, Lung and Blood (K12-HL141952) and the National Institute of General Medical Sciences (T32-GM008763, T32-GM080189). Human brain tissue was provided by the Johns Hopkins Alzheimer’s Disease Research Center.

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