In a "reverse engineering" study using the brain tissues of five people who died of Alzheimer's disease, researchers at Johns Hopkins Medical School said they found that a special sugar molecule may play an important role in the development of Alzheimer's disease** Scientists say that if this discovery is confirmed by further research, this molecule called glycan can be used as a new target for early diagnosis, testing, treatment and possibly even prevention of Alzheimer's disease.
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It is reported that this study was recently published in the Journal of biological chemistry.
Alzheimer's disease is the most common form of dementia in the United States. It is estimated that 5.8 million Americans are affected. This progressive disease occurs when nerve cells in the brain die due to the accumulation of harmful forms of proteins called amyloid and tau.
Cleaning up these pathogenic forms of amyloid and tau proteins is the work of brain immune cells called microglia. Early studies have found that Alzheimer's disease is more likely to occur when cleanup is impaired. In some people, this is caused by an excess of a receptor called CD33 on microglia.
Dr. Ronald schnaar, Professor of pharmacology at John Jacob Abel of Johns Hopkins University School of medicine and director of the laboratory leading the study, pointed out: "the receptors themselves are not active. Something needs to be connected with them to prevent microglia from cleaning up these toxic proteins in the brain."
Previous studies by researchers have shown that these "connector" molecules are special sugars for CD33. Scientists call them glycans. These molecules are made up of specialized proteins that travel through cells to help them find the right receptors. The protein glycan combination is called glycoprotein.
To find out which specific glycoprotein is linked to CD33, schnaar's team obtained the brain tissues of five people who died of Alzheimer's disease and five people who died of other causes from the Johns Hopkins University Alzheimer's disease research center. The results showed that only one of the thousands of glycoproteins they collected from brain tissue was linked to CD33.
To identify this mysterious glycoprotein, researchers first need to separate it from other brain glycoproteins. Since it is the only glycoprotein in the brain that is linked to CD33, they used this feature to "capture" it and separate it.
Sugars are composed of various sugars that affect molecular interactions. This sugar can be identified by its components. The researchers used chemical tools to deconstruct sugars step by step and listed the identity and order of their building blocks. The researchers identified the carbohydrate portion of the glycoprotein as silicosilicated keratin.
Then, researchers use mass spectrometry to determine the "fingerprint" of protein components to determine their identity, and mass spectrometry can identify the building blocks of proteins. By comparing the molecular composition of proteins with the database of known protein structures, the research team concluded that the protein part of glycoproteins is receptor tyrosine phosphatase (rptp) zeta.
The researchers named the combined glycoprotein structure rptp zeta S3L.
The team had previously found the same carbohydrate "signature" on a protein that controls airway allergic reactions, and destroying this carbohydrate would inhibit allergic reactions in mice.
Dr. Anabel Gonzalez Gil Alvarenga, postdoctoral fellow of schnaar laboratory and the first author of the study, said: "we suspect that the glycan characteristics carried on rptp zeta may have a similar role in inactivating microglia through CD33."
Further experiments showed that the number of rptp zeta S3L in the brain tissue of five people who died of Alzheimer's disease was more than twice that of donors who did not have the disease. This means that the glycoprotein may be linked to more CD33 receptors than a healthy brain, which limits the brain's ability to clean up harmful proteins.
"Identifying this unique glycoprotein provides a step for finding new drug targets and possible early diagnosis of Alzheimer's disease," Gonzalez Gil said
Next, the researchers plan to further study the structure of rptp zeta S3L to determine how its attached sugars enable glycoproteins to have a unique ability to interact with CD33.