In a bit of “reverse engineering” research involving brain tissue from five people who died of Alzheimer’s disease, researchers at Johns Hopkins Medicine say they found that a special sugar molecule could play a key role in the development of Alzheimer’s disease. If further research confirms the finding, the molecule, known as a glycan, could serve as a new target for early diagnostic tests, treatments and perhaps prevention of Alzheimer’s disease, the researchers say.
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. The progressive condition, which affects an estimated 5.8 million Americans, occurs when nerve cells in the brain die due to the buildup of harmful forms of proteins called amyloid and tau.
Clearing the disease-causing forms of amyloid and tau is the job of the brain’s immune cells called microglia. Previous studies have shown that Alzheimer’s disease is more likely to occur when clearance is hindered. In some people, this is caused by an overabundance of a receptor on the microglial cells called CD33.
“Receptors aren’t active on their own. Something has to be connected to them to prevent microglia from clearing these toxic proteins in the brain, says Ronald Schnaar, Ph.D., the John Jacob Abel Professor of Pharmacology at Johns Hopkins University School of Medicine.” Medicine and director of the lab that led the study.
Previous studies by the researchers showed that these “connector” molecules for CD33 are special sugars. Known to scientists as glycans, these molecules are transported around the cell by specialized proteins that help them find the right receptors. The protein-glycan combination is called a glycoprotein.
In an effort to find out which specific glycoprotein is linked to 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. Among the many thousands glycoproteins they collected from the brain tissues, only one linked to CD33.
To identify this mysterious glycoprotein, the researchers first had to separate it from the other brain glycoproteins. Since it was the only one in the brain to attach to CD33, they used this feature to “catch” and separate it.
Glycans are made up of different sugar building blocks that influence the interactions of the molecule. Such sugars can be identified by their component parts. The researchers used chemical tools to deconstruct the glycan step by step and establish the identity and sequence of the building blocks. The researchers identified the glycan portion of the glycoprotein as sialylated keratan sulfate.
Next, the researchers determined the identity of the protein component by taking its “fingerprint” using mass spectroscopy, which identifies protein building blocks. 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 receptor tyrosine phosphatase (RPTP) was zeta.
The researchers named the combined glycoprotein structure RPTP zeta S3L.
The group had previously found the same glycan “signature” on a protein that regulates allergic responses in the airways, and that disrupting the glycan dampened allergic responses in mice.
We suspect that the glycan signature carried by RPTP zeta may play a similar role in deactivating microglia via CD33.”
Anabel Gonzalez-Gil Alvarenga, Ph.D., postdoctoral researcher in the Schnaar Laboratory and lead author of the study
Further experiments showed that the brain tissue of the five people who died of Alzheimer’s disease had more than twice as much RPTP zeta S3L as the donors who did not have the disease. This means that this glycoprotein may connect to more CD33 receptors than a healthy brain, limiting the brain’s ability to clear out harmful proteins.
“Identifying this unique glycoprotein offers a step toward finding new drug targets and potentially early diagnosis for Alzheimer’s disease,” says Gonzalez-Gil.
Next, the researchers plan to further study the structure of RPTP zeta S3L to determine how the attached glycans give the glycoprotein its unique ability to interact with CD33.
Gonzalez-Gil, A., et al. (2022) Human brain sialoglycan ligand for CD33, a microglial inhibitory Siglec implicated in Alzheimer’s disease. Journal of Biological Chemistry† doi.org/10.1016/j.jbc.2022.101960†
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