A special sugar particle has been found by Johns Hopkins Medicine researchers that might play a crucial function in the development of Alzheimers disease.
In a little bit of “reverse engineering” research study using brain tissues from five individuals who passed away with Alzheimers illness, Johns Hopkins Medicine researchers say they have actually found that an unique sugar molecule could play a crucial function in the advancement of Alzheimers disease. If the finding is verified by further research study, the molecule, understood as a glycan, might function as a new target for early diagnostic tests, treatments, and perhaps even avoidance of Alzheimers illness, state the researchers.
The study was released recently in the Journal of Biological Chemistry.
In the United States, Alzheimers illness is the most typical form of dementia. Impacting an estimated 5.8 million Americans, the progressive condition happens when afferent neuron in the brain die from the buildup of hazardous kinds of proteins called amyloid and tau.
Cleaning up these disease-causing types of amyloid and tau is the task of the brains immune cells, called microglia. Earlier research study found that Alzheimers illness is more likely to occur when clean-up is impaired. Previous studies by the researchers showed that for CD33, these “adapter” particles are unique sugars. The researchers utilized chemical tools to deconstruct the glycan step by step, laying out the identity and order of its structure blocks. The researchers identified the glycan portion of the glycoprotein as sialylated keratan sulfate.
Tidying up these disease-causing types of amyloid and tau is the task of the brains immune cells, called microglia. When cleanup is impaired, earlier research discovered that Alzheimers disease is more likely to occur. In some individuals, this is triggered by a surplus of a receptor on the microglia cells, called CD33.
” Receptors are not active on their own. Something needs to get in touch with them to block microglia from tidying up these hazardous proteins in the brain, says 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 research study.
Previous studies by the scientists revealed that for CD33, these “port” molecules are unique sugars. Known to scientists as glycans, these molecules are transported around the cell by specialized proteins that assist them find their proper receptors. The protein-glycan combination is called a glycoprotein.
In a quote to discover out which particular glycoprotein links with CD33, Schnaars research study group gotten brain tissue from 5 people who died of Alzheimers disease and from 5 individuals who passed away from other causes from the Johns Hopkins Alzheimers Disease Research. Amongst the lots of thousands of glycoproteins they collected from the brain tissues, just one connected to CD33.
To recognize this mystery glycoprotein, the researchers first required to separate it from the other brain glycoproteins. Given that it was the only one in the brain that attached itself to CD33, they used this function to “capture” it and separate it.
Glycans are comprised of various sugar foundation that influence the molecules interactions. Such sugars can be identified by their element parts. The scientists used chemical tools to deconstruct the glycan step by action, setting out the identity and order of its structure blocks. The researchers identified the glycan portion of the glycoprotein as sialylated keratan sulfate.
Then, the scientists identified the protein parts identity by taking its “fingerprint” using mass spectroscopy, which determines protein foundation. By comparing the molecular makeup of the protein with a database of recognized protein structures, the research study team was able to conclude the protein portion of the glycoprotein was receptor tyrosine phosphatase (RPTP) zeta.
The researchers called the combined glycoprotein structure RPTP zeta S3L.
The group had actually previously found the same glycan “signature” on a protein that manages allergic reactions in the respiratory tract, and that interrupting the glycan moistened allergic actions in mice.
” We presume the glycan signature carried on RPTP zeta might have a comparable role in deactivating microglia through CD33,” says Anabel Gonzalez-Gil Alvarenga, Ph.D., postdoctoral fellow in the Schnaar laboratory and first author of the research study.
Further experiments showed that the brain tissue of the 5 individuals who passed away with Alzheimers illness had more than two times as much RPTP zeta S3L as the donors who did not have the illness. This suggests that this glycoprotein may be getting in touch with more CD33 receptors than a healthy brain, limiting the brains capability to clean up harmful proteins.
” Identifying this distinct glycoprotein supplies a step towards finding new drug targets and potentially early diagnostics for Alzheimers disease,” states Gonzalez-Gil.
Next, the scientists plan to additional research study RPTP zeta S3Ls structure to figure out how its attached glycans give the glycoprotein its unique ability to connect with CD33.
Reference: “Human brain sialoglycan ligand for CD33, a microglial repressive Siglec implicated in Alzheimers illness” by Anabel Gonzalez-Gil, Ryan N. Porell, Steve M. Fernandes, Eila Maenpaa, T. August Li, Tong Li, 19 April 2022, Journal of Biological Chemistry.www.jbc.org/ article/S0021 -9258( 22 )00400-8.
Other researchers associated with this research study consist of Ryan Porell, Steve Fernandes, Eila Maenpaa, T. August Li, Tong Li, Philip Wong, Zaikuan Yu, Benjamin Orsburn and Namandjé Bumpus of the 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 Heart, Lung, and Blood Institute (K12-HL141952) and the National Institute of General Medical Sciences (T32-GM008763, T32-GM080189). Human brain tissues were supplied by the Johns Hopkins Alzheimers Disease Research.
