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Investigating abnormal protein structures in Alzheimer's and other diseases

UW researchers work to create new diagnostic test for Alzheimer’s via early protein formation

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Alzheimer’s disease is the most common cause of dementia and is an “irreversible, progressive brain disorder that slowly destroys memory and thinking skills,” according to the National Institute on Aging. It is characterized by the abnormal function of two proteins known as beta-amyloid and tau. 

According to the National Institute on Aging, during Alzheimer’s disease, beta-amyloid proteins clump together and are deposited in the brain in the form of a plaque, while tau proteins also begin sticking together and, among other things, block communication between neurons, which are brain cells that use electrical and chemical signals to communicate. 

Dr. Valerie Daggett is a researcher in the UW department of bioengineering using computational and experimental methods to create new diagnostic techniques and therapeutics for amyloid diseases, such as Alzheimer’s disease. One focus of her research group is the involvement of the uncommon protein alpha sheet structure during amyloid diseases. 

In biological processes, the structure of different molecules is critical for their functions. Normally there are two main structural components of proteins: the alpha helix, which “looks sort of like a slinky,” according to Daggett, and the beta sheet, in which a few strands of the protein line up with one another and look similar to pleats. The alpha sheet structure is neither of these and is just slightly different from the beta sheet structure.

Using computer modeling, Daggett realized that the alpha sheet structure was frequently found in disease-associated forms of proteins but absent from most normal proteins. Over the past few years, she has worked to elucidate the actions of the alpha sheet structure in disease.

One of her recent projects has been understanding the actions of alpha sheet peptides during Alzheimer’s disease and developing a diagnostic test. Dr. Dylan Shea, a previous graduate student in her research group, published a paper in 2019 showing that beta-amyloid, one of the proteins involved in Alzheimer’s disease, temporarily changed its structure to alpha sheet early in the process and prior to deposition as a plaque. 

The change of beta-amyloid’s structure to alpha-sheet caused the protein to become toxic and cause significant damage to cells. Additionally, Shea also found that he could design synthetic alpha sheet peptides that would bind the alpha sheet structure of beta-amyloid, preventing some of the consequences, such as cell death.

Currently, there is no way to treat Alzheimer’s disease and it’s difficult to diagnose in an early stage, before significant damage is done. Many of the modern diagnostic and treatment methods target either the beta-amyloid plaques or tau protein, but elevated levels are rarely observable until after major damage has already been done in the brain. Shea’s work indicated that the early formation of alpha sheet beta-amyloid could be targeted for both diagnostic and therapeutic purposes. 

“It's really my opinion that they’re just going after the wrong targets; they're going after the normal form which we need for normal brain function,” Daggett said. “[Plaques form] 10 to 20 years after you've got the toxic [alpha sheet] oligomers attacking the brain, and there's many other downstream pathways that become engaged when the toxic oligomers form.”

Now, Daggett is collaborating with Dr. Elaine Peskind’s group at the UW School of Medicine to create a diagnostic kit for Alzheimer’s disease that targets the early alpha sheet structure of beta-amyloid. By fine-tuning the test until it could detect even tiny amounts of the alpha sheet oligomers, they are hoping to use plasma instead of cerebrospinal fluid to identify the onset of Alzheimer’s disease. 

“We'd get the samples, you know, all these little tubes with codes that were indecipherable,” Dagget said. “[Then you] go run them and see them partition out and you're like, oh my God, this works.”

From computer predictions to a testing plasma, this work regarding alpha sheet structure has been crucial in creating Dagget’s new diagnostic test. Beyond Alzheimer’s disease, Daggett also hopes to create a similar test for other neurodegenerative diseases, such as Parkinson’s disease. Some of her other research targets include Type 2 diabetes, organisms that create amyloid-containing biofilms, and, recently, cancers associated with the alpha-sheet structure.

Reach contributing writer Irika Sinha at Twitter: @irikasinha 

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