A sugar-containing protein associated with Alzheimer’s disease

Summary: Glycan, especially sugar protein, appears to play a major role in the development of Alzheimer’s disease.

A source: Johns Hopkins University

In a small “reverse engineering” study using the brain tissue of five people who died of Alzheimer’s disease, Johns Hopkins Medicine researchers found that a particular sugar molecule could play a key role in the development of Alzheimer’s disease.

Scientists say that if further research confirms the findings, a molecule called glycan could serve as a new target for early diagnostic tests, treatment and possibly prevention of Alzheimer’s disease.

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

Alzheimer’s disease is the most common form of deficiency in the United States. A progressive disorder that affects approximately 5.8 million Americans occurs when nerve cells in the brain die due to the accumulation of harmful forms of proteins called amyloids and minerals.

Purification of amyloid and mountain pathogens is the work of immune cells in the brain called microglia. Previous studies have shown that Alzheimer’s disease can occur when cleaning is disrupted. In some people, this is due to an overabundance of receptors in microglia cells called CD33.

“Receptors are not active on their own. Ronald Schnaar, professor of pharmacology and laboratory director at Johns Hopkins University School of Medicine, Ph.D. Ronald Schnaar says. to read.

Studies by researchers have shown that these “binding” molecules are unique to CD33. These molecules, known to scientists as glycans, move around the cell using special proteins to help them find the right receptors. The protein-glycan combination is called glycoprotein.

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

To identify this mysterious glycoprotein, researchers first had to isolate it from other glycoproteins in the brain. Because it is the only one in the brain connected to CD33, they used this function to “catch” and isolate it.

Glycans are made up of various building blocks of sugar that affect the way molecules interact. Such sugars can be identified by their components.

Using chemical weapons, the researchers deconstructed the glycan in stages to determine the identity and order of its building blocks. Scientists have identified the glycan portion of glycoprotein as sialized keratin sulfate.

The researchers then identified the protein component by taking a “fingerprint” of the protein using mass spectroscopy to identify its building blocks.

Comparing the molecular composition of the protein with a database of known protein structures, the team was able to conclude that the protein portion of the glycoprotein is the receptor tyrosine phosphatase (RPTP) zeta.

The researchers called the combined glycoprotein structure RPTP zeta S3L.

Purification of amyloid and mountain pathogens is the work of immune cells in the brain called microglia. Image in public domain

The group previously found a “signature” of the same glycine in a protein that controlled allergic reactions in the respiratory tract, and glycine degradation slowed allergic reactions in mice.

Anabel Gonzalez-Gil Alvarenga, Ph.D., PhD, Schnaar Laboratory PhD and first author of the study, said: “We suspect that the glycan signature in the RPTP zeta may play a similar role in the deactivation of microglia by CD33.”

Further experiments showed that five people who died of Alzheimer’s disease had twice as much RPTP zeta S3L in their brain tissue as from disease-free donors.

This means that glycoprotein binds to more CD33 receptors than in a healthy brain, limiting the brain’s ability to clear harmful proteins.

“The detection of this unique glycoprotein is a step towards finding new drug targets and 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 in it give the glycoprotein its unique ability to interact with CD33.

See also

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Research on Alzheimer’s disease

Author: Press service
A source: Johns Hopkins University
The connection: Press Service – Johns Hopkins University
Photo: Image in public domain

Original study: Open access.
“Siglec microglial inhibitor associated with Alzheimer’s disease, for sialoglycan ligand CD33 in the human brain” by Anabel Gonzalez-Gil et al. Journal of Biological Chemistry


Abstract

The human brain sialoglycan ligand for CD33, a Siglec microglial inhibitor associated with Alzheimer’s disease.

Alzheimer’s disease (AD) is characterized by the accumulation of improperly folded proteins. Genetic studies include microglia in the pathogenesis of AD, and phagocytic immune cells living in the brain. As positive effects, microglia purify toxic proteins, while negative effects release anti-inflammatory mediators. An imbalance of these functions contributes to the progression of AD.

Human CD33 polymorphisms, inhibitory microglial receptors, associated with AD sensitivity; High CD33 expression is associated with an increased risk of AD. CD33, also called Siglec-3, is a member of the immunoglobulin-type lectin (Siglec) family, which binds to immune-regulating receptors to sialic acid. Siglec-mediated inhibition begins with binding of complementary sialoglycan ligands in the tissue environment.

Here, we identify a sialoglycoprotein that binds to CD33 in the human cerebral cortex, as well as Siglec-8, the most common in human microglia. Ligand, we call it the protein tyrosine phosphatase zeta receptor (RPTPζ).S3LRPTPζ (phosphacan) consists of sialized keratin sulphate chains transported in a small isoform / glycorform and is found in the extracellular environment of the parenchyma of the human brain.

RPTPζ was twice as high in the brains of human AD donorsS3L Increased RPTPζ capacity compared to age-matched control donorsS3L Excessive expression limits the clearance of a protein that contributes to AD pathology.

Siglec-F in mice represents the same structure that binds to mice and is the RPTPζ isoform of sialized keratin sulfate that reacts crosswise with human CD33 and Siglec-8.

Mice brains were developed for RPTPζ, sialyltransferase deficiency St3gal4or keratan sulfate sulfotransferase Chst1 There is no Siglec bond that makes up the ligand structure.

Unique CD33 and Siglec-8 ligand, RPTPζS3LAD can contribute to progress.

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