Gamechanging study finds that sugar is critical to the prevention and cure of Alzheimer's
[Apr. 25, 2023: JD Shavit, The Brighter Side of News]
Researchers say they discovered that a special sugar molecule could play a key role in the development of Alzheimer’s disease. (CREDIT: Creative Commons)
In a promising development for Alzheimer’s disease research, scientists from Johns Hopkins Medicine have identified a sugar molecule that may play a crucial role in the development of the disease. The team of researchers found that a specific type of glycan, a complex sugar molecule, could be a new target for early diagnostic tests, treatments, and possibly prevention of Alzheimer’s disease.
The study, which was published in the Journal of Biological Chemistry, used brain tissue samples from five people who had died with Alzheimer’s disease. The researchers discovered that the glycoprotein RPTP zeta S3L was connecting to more CD33 receptors than healthy brains, limiting the brain’s ability to clean up harmful proteins.
Alzheimer’s disease is a progressive disorder that affects an estimated 5.8 million Americans, causing nerve cells in the brain to die due to the buildup of harmful proteins called amyloid and tau. The brain’s immune cells, called microglia, are responsible for cleaning up the disease-causing forms of amyloid and tau. When this process is impaired, Alzheimer’s disease is more likely to occur.
“Receptors are not active on their own. Something needs to connect with them to block microglia from cleaning up these toxic proteins in the brain,” said Ronald Schnaar, Ph.D., the John Jacob Abel Professor of Pharmacology at the Johns Hopkins University School of Medicine and director of the laboratory that led the study.
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Past studies by the researchers showed that for CD33, these “connector” molecules are special sugars known as glycans, which are ferried around the cell by specialized proteins that help them find their appropriate receptors.
To identify the specific glycoprotein that connects with CD33, Schnaar’s research team obtained brain tissue from five people who had died of Alzheimer’s disease and from five people who had died from other causes from the Johns Hopkins Alzheimer’s Disease Research Center. Among the many thousands of glycoproteins they gathered from the brain tissues, only one connected to CD33.
The researchers used chemical tools to deconstruct the glycan step by step, laying out the identity and order of its building blocks. The researchers identified the glycan portion of the glycoprotein as sialylated keratan sulfate and determined the protein component’s identity by taking its “fingerprint” using mass spectroscopy.
Human brain CD33/Siglec-8 ligand is distributed throughout the cerebral cortex parenchyma. (CREDIT: Journal of Biological Chemistry)
By comparing the molecular makeup 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 receptor tyrosine phosphatase (RPTP) zeta. The researchers named the combined glycoprotein structure RPTP zeta S3L.
“We suspect the glycan signature carried on RPTP zeta may have a similar role in deactivating microglia through CD33,” said Anabel Gonzalez-Gil Alvarenga, Ph.D., postdoctoral fellow in the Schnaar laboratory and first author of the study.
Further experiments showed that the brain tissue of the five people who had died with Alzheimer’s disease had more than twice as much RPTP zeta S3L as the donors who did not have the disease.
The same glycoform of RPTPζ carries CD33 and Siglec-8 ligands. A, equal aliquots of human cerebral cortex total protein extract from four donors (numbered) were resolved on replicate composite agarose–acrylamide gels and blotted to PVDF. (CREDIT: Journal of Biological Chemistry)
“Identifying this unique glycoprotein provides a step toward finding new drug targets and potentially early diagnostics for Alzheimer’s disease,” said Gonzalez-Gil.
Next, the researchers plan to further study RPTP zeta S3L’s structure to determine how its attached glycans give the glycoprotein its unique ability to interact with CD33.
The potential implications of this research are vast. Currently, Alzheimer's disease is diagnosed through the use of brain scans, cognitive tests, and evaluations of a patient's symptoms. However, these methods are not foolproof, and they do not provide early detection of the disease.
If the glycan molecule identified by the Johns Hopkins researchers can indeed be used as a diagnostic marker, doctors could use it to identify Alzheimer's disease much earlier than is currently possible. This would allow for earlier treatment, potentially slowing or even stopping the progression of the disease.
Furthermore, the identification of this glycoprotein provides a potential target for the development of new treatments for Alzheimer's disease. Currently, there are no drugs that can cure or even halt the progression of the disease. Most treatments focus on managing symptoms rather than targeting the underlying cause.
If researchers can develop drugs that target the glycoprotein identified by the Johns Hopkins team, it could lead to the development of more effective treatments that target the root cause of Alzheimer's disease.
The research team at Johns Hopkins is not the only one exploring the role of glycans in Alzheimer's disease. Other research teams have also identified specific glycans that are associated with the disease.
For example, a team of researchers at the University of Manchester in the UK identified a specific glycan that is present in the brains of people with Alzheimer's disease. This glycan is found on a protein called amyloid beta, which is a major component of the amyloid plaques that are a hallmark of Alzheimer's disease.
Mouse brain Siglec-F ligand coelutes with Siglec-8 binding and is purified by Siglec-8-Fc affinity capture. (CREDIT: Journal of Biological Chemistry)
The Manchester researchers found that this glycan causes amyloid beta to clump together, forming larger plaques. This, in turn, leads to inflammation and the death of brain cells, contributing to the development of Alzheimer's disease.
Other research has focused on the role of glycans in the immune system. Glycans are known to play an important role in the immune response, and researchers believe that they may also be involved in the development of Alzheimer's disease.
The identification of specific glycans associated with Alzheimer's disease opens up new avenues for research into the causes and potential treatments of the disease. While there is still much to be learned about the role of glycans in Alzheimer's disease, the work being done by researchers at Johns Hopkins and other institutions is an important step forward in the fight against this devastating illness.
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