Valerie Daggett – 91�� News

15 91�� professors among new class of members to the Washington State Academy of Sciences

James Urton — Thu, 01 Aug 2024 18:46:33 +0000

UPDATE (Aug. 2, 2024): A previous version of this story misstated Paul Kinahan’s name.

Fifteen faculty members at the 91�� have been elected to the Washington State Academy of Sciences. They are among 36 scientists and educators from across the state . Selection recognizes the new members’ “outstanding record of scientific and technical achievement, and their willingness to work on behalf of the academy to bring the best available science to bear on issues within the state of Washington.”

Twelve 91�� faculty members were selected by current WSAS members. They are:

, associate professor of epidemiology, of health systems and population health, and of child, family and population health nursing, who “possesses the rare combination of scientific rigor and courageous commitment to local community health. Identifying original ways to examine questions, and seeking out appropriate scientific methods to study those questions, allow her to translate research to collaborative community interventions with a direct impact on the health of communities.”
, the Shauna C. Larson endowed chair in learning sciences, for “his work in the cultural basis of scientific research and learning, bringing rigor and light to multiculturalism in science and STEM education through STEM Teaching Tools and other programs.”
, professor of psychiatry and behavioral sciences, “for her sustained commitment to community-engaged, science-driven practice and policy change related to the prevention of suicide and the promotion of mental health, with a focus on providing effective, sustainable and culturally appropriate care to people with serious mental illness.”
, the David and Nancy Auth endowed professor in bioengineering, who has “charted new paths for 30-plus years. Her quest to deeply understand protein folding/unfolding and the link to amyloid diseases has propelled her to pioneer unique computational and experimental methods leading to the discovery and characterization of a new protein structure linked to toxicity early in amyloidogenesis.”
, professor of environmental and occupational health sciences, of global health, and of emergency medicine, who is “a global and national leader at the intersection of climate change and health whose work has advanced our understanding of climate change health effects and has informed the design of preparedness and disaster response planning in Washington state, nationally and globally.”
, professor of bioengineering and of radiology, who is “recognized for his contributions to the science and engineering of medical imaging systems and for leadership in national programs and professional and scientific societies advancing the capabilities of medical imaging.”
, the Donald W. and Ruth Mary Close professor of electrical and computer engineering and faculty member in the 91�� Clean Energy Institute, who is “recognized for his distinguished research contributions to the design and operation of economical, reliable and environmentally sustainable power systems, and the development of influential educational materials used to train the next generation of power engineers.”
, senior vice president and director of the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Center, the Joel D. Meyers endowed chair of clinical research and of vaccine and infectious disease at Fred Hutch, and 91�� professor of medicine, who is “is recognized for her seminal contributions to developing validated laboratory methods for interrogating cellular and humoral immune responses to HIV, TB and COVID-19 vaccines, which has led to the analysis of more than 100 vaccine and monoclonal antibody trials for nearly three decades, including evidence of T-cell immune responses as a correlate of vaccine protection.”
, professor of political science and the Walker family professor for the arts and sciences, who is a specialist “in environmental politics, international political economy, and the politics of nonprofit organizations. He is widely recognized as a leader in the field of environmental politics, best known for his path-breaking research on the role firms and nongovernmental organizations can play in promoting more stringent regulatory standards.”
, the Ballmer endowed dean of social work, for investigations of “how inequality, in its many forms, affects health, illness and quality of life. He has developed unique conceptual frameworks to investigate how race, ethnicity and immigration are associated with health and social outcomes.”
, professor of chemistry, who is elected “for distinguished scientific and community contributions to advancing the field of electron paramagnetic resonance spectroscopy, which have transformed how researchers worldwide analyze data.”
, professor of bioengineering and of ophthalmology, whose “pioneering work in biomedical optics, including the invention of optical microangiography and development of novel imaging technologies, has transformed clinical practice, significantly improving patient outcomes. Through his numerous publications, patents and clinical translations, his research has helped shape the field of biomedical optics.”

Three new 91�� members of the academy were selected by virtue of their previous election to one of the National Academies. They are:

, professor of atmospheric and climate science, who had been elected to the National Academy of Sciences “for contributions to research and expertise in atmospheric radiation and cloud processes, remote sensing, cloud/aerosol/radiation/climate interactions, stratospheric circulation and stratosphere-troposphere exchanges and coupling, and climate change.”
, the Bartley Dobb professor for the study and prevention of violence in the Department of Epidemiology and a 91�� professor of pediatrics, who had been elected to the National Academy of Medicine “for being a national public health leader whose innovative and multidisciplinary research to integrate data across the health care system and criminal legal system has deepened our understanding of the risk and consequences of firearm-related harm and informed policies and programs to reduce its burden, especially among underserved communities and populations.”
, division chief of general pediatrics at Seattle Children’s Hospital and a 91�� professor of pediatrics, who had been elected to the National Academy of Medicine “for her leadership in advancing child health equity through scholarship in community-partnered design of innovative care models in pediatric primary care. Her work has transformed our understanding of how to deliver child preventive health care during the critical early childhood period to achieve equitable health outcomes and reduce disparities.”

In addition, Dr. , president and director of the Fred Hutchinson Cancer Center and of the Cancer Consortium — a partnership between the 91��, Seattle Children’s Hospital and Fred Hutch — was elected to the academy for being “part of a research effort that found mutations in the cell-surface protein epidermal growth factor receptor (EGFR), which plays an important role in helping lung cancer cells survive. Today, drugs that target EGFR can dramatically change outcomes for lung cancer patients by slowing the progression of the cancer.”

the Boeing-Egtvedt endowed professor and chair in aeronautics and astronautics, will join the board effective Sept. 30. Morgansen was elected to WSAS in 2021 “for significant advances in nonlinear methods for integrated sensing and control in engineered, bioinspired and biological flight systems,” and “for leadership in cross-disciplinary aerospace workforce development.” She is currently director of the Washington NASA Space Grant Consortium, co-director of the 91�� Space Policy and Research Center and chair of the AIAA Aerospace Department Chairs Association. She is also a member of the WSAS education committee.

“I am excited to serve on the WSAS board and work with WSAS members to leverage and grow WSAS’s impact by identifying new opportunities for WSAS to collaborate and partner with the state in addressing the state’s needs,” said Morgansen.

The new members to the Washington State Academy of Sciences will be formally inducted in September.

Q&A: How a potential treatment for Alzheimer’s disease could also work for Type 2 diabetes

Sarah McQuate — Thu, 29 Feb 2024 18:25:07 +0000

Of the at least 90% have Type 2, according to the Centers for Disease Control and Prevention. Type 2 diabetes occurs over time and is characterized by a loss of the cells in the pancreas that make the hormone insulin, which helps the body manage sugar.

These cells make another protein, called islet amyloid polypeptide or IAPP, which has been found clumped together in many Type 2 diabetes patients. The formation of IAPP clusters is comparable to how a to eventually form the signature plaques associated with that disease.

Valerie Daggett

Researchers at the 91�� have demonstrated more similarities between IAPP clusters and those in Alzheimer’s. The team previously showed that a synthetic peptide can block the formation of small, toxic Alzheimer’s protein clusters. Now, in a in Protein Science, the researchers used a similar peptide to block the formation of IAPP clusters.

91�� News asked co-senior author , a 91�� professor of bioengineering and faculty member in the 91�� , for details about protein aggregation and how these synthetic peptides work.

Alzheimer’s and Type 2 diabetes are part of a family of diseases that are characterized by having proteins that cluster together. What’s happening?

Valerie Daggett: There are over 50 of these amyloid diseases, and they start out with their respective proteins in their biologically active, good form. But then the proteins start changing structure and globbing together. These aggregates can be different sizes. They can have different underlying structures and different effects on the cells around them.

Early in the process there are smaller clusters, which are toxic, and they set off all kinds of problems. This leads to a very complicated disease because lots of other things go awry in response to these toxic clusters. Over time, these clusters combine to form non-toxic structures: longer strands and finally large deposits, such as the Alzheimer’s plaques.

Many people know that protein aggregation plays a role in neurodegenerative diseases, such as Alzheimer’s disease. Can you describe what’s happening here?

Valerie Daggett will deliver this year’s University Faculty Lecture at 5:30 p.m. on Monday, April 1.

VD: In the case of Alzheimer’s, these small, toxic protein clusters are running around the brain attacking neurons and then over time there’s enough damage that we start to see symptoms. By the time these clusters have combined to form the non-toxic plaques, there’s already been a lot of damage. It becomes similar to trying to treat stage 4 cancer. That’s why we want to get in early.

What’s happening with Type 2 diabetes?

VD: It’s similar, except it’s happening in the pancreas instead of the brain. In healthy people, cells in the pancreas, called beta cells, secrete IAPP along with insulin. The normal, active form of IAPP helps with metabolism maintenance. But when IAPP changes shape, it starts to form these toxic clusters and then it starts attacking the beta cells. And these clusters are equal-opportunity toxins. We, and many others, have shown that you can put them on different cell types and they will kill the cells.

In this paper, you show that the IAPP clusters go through an “” phase. What does this mean and why is it significant?

VD: We’ve been looking at these amyloid systems for a long time and we started seeing this weird protein structure. It’s like every other one of the protein building blocks, called amino acids, has had this crankshaft motion on it. Half of them are rotated the wrong way.

At first we thought: “That’s got to be an artifact. Nobody discovers a new structure.” But we’ve since shown that this “alpha sheet” structure is real. And proteins in all the amyloid systems we’ve looked at — 14 now including Type 2 diabetes — form these alpha sheet structures when they’re in these small, toxic clusters. No one had seen that for IAPP before this paper.

Also in this paper, you showed that a synthetic peptide was able to bind and neutralize the toxic IAPP clusters and keep beta cells alive. What’s special about this peptide and how does it work?

VD: Previously, we designed synthetic peptides to bind to the toxic protein clusters in Alzheimer’s disease. The idea here is for these peptides to take these clusters out of commission before they can wreak havoc on the cells. The peptide we made also forms an alpha sheet structure, but it is not toxic to the cells. It binds really tightly to the clusters, and we’re currently studying what happens to the clusters after it binds.

In this paper, we showed that our synthetic peptides also work against the toxic IAPP clusters, which means this could be a potential therapeutic in the future.

Type 2 diabetes is the most prevalent amyloid disease — it affects . A lot of people associate Type 2 diabetes treatment with changing lifestyle measures, but that doesn’t work for everyone. A drug that could help minimize the damage IAPP does to the pancreas could be really helpful.

Microscopy image of beta cells making IAPP (left) and IAPP plus one of the team’s synthetic peptides (right). The synthetic peptides bind to the small toxic IAPP clusters to take them out of commission before they can wreak havoc on the cells. This binding also prevents the clusters from combining to form larger non-toxic structures, such as longer strands and finally large deposits. Shown here, the cells without the synthetic peptide (left) have more of those larger structures (more green) than the cells with the synthetic peptide (right, less green). Other colors in these images are labeling insulin (red) and cell nuclei (blue). Photo: Hsu et al./Protein Science

This paper had two lead authors: , who completed this research as a 91�� doctoral student of molecular engineering and is now at Columbia University, and , who completed this research as an acting instructor of medicine in the 91�� School of Medicine and is now at Indiana University. Additional co-authors on this paper are Tatum Prosswimmer, a 91�� doctoral student of molecular engineering; , who completed this research as a 91�� doctoral student of molecular engineering and is now at Ambit Inc; , who completed this research as a 91�� undergraduate student majoring in biochemistry and is now a student at Pacific Northwest University of Health Sciences; , who completed this research as a senior research scientist in the Division of Metabolism, Endocrinology and Nutrition in the 91�� School of Medicine and is now at Tacoma Community College; and , professor of medicine in the 91�� School of Medicine.

This research was funded by the National Institutes of Health, the 91�� Office of Research, the 91�� Department of Bioengineering, the Department of Veterans Affairs, the American Diabetes Association and a 91�� Mary Gates Research Scholarship.

For more information, contact Daggett at daggett@uw.edu.

New blood test can detect ‘toxic’ protein years before Alzheimer’s symptoms emerge, study shows

James Urton — Mon, 05 Dec 2022 20:01:04 +0000

Today, by and large, patients receive a diagnosis of Alzheimer’s only after they exhibit well-known signs of the disease, such as memory loss. By that point, the best treatment options simply slow further progression of symptoms.

But research has shown that the seeds of Alzheimer’s are planted years — even decades — earlier, long before the cognitive impairments surface that make a diagnosis possible. Those seeds are amyloid beta proteins that misfold and clump together, forming small aggregates called oligomers. Over time, through a process scientists are still trying to understand, those “toxic” oligomers of amyloid beta are thought to develop into Alzheimer’s.

A team led by researchers at the 91�� has developed a laboratory test that can measure levels of amyloid beta oligomers in blood samples. As they report in a published Dec. 9 in the Proceedings of the National Academy of Sciences, their test — known by the acronym SOBA — could detect oligomers in the blood of patients with Alzheimer’s disease, but not in most members of a control group who showed no signs of cognitive impairment at the time the blood samples were taken.

However, SOBA did detect oligomers in the blood of 11 individuals from the control group. Follow-up examination records were available for 10 of these individuals, and all were diagnosed years later with mild cognitive impairment or brain pathology consistent with Alzheimer’s disease. Essentially, for these 10 individuals, SOBA had detected the toxic oligomers before symptoms surfaced.

“What clinicians and researchers have wanted is a reliable diagnostic test for Alzheimer’s disease — and not just an assay that confirms a diagnosis of Alzheimer’s, but one that can also detect signs of the disease before cognitive impairment happens. That’s important for individuals’ health and for all the research into how toxic oligomers of amyloid beta go on and cause the damage that they do,” said senior author , a 91�� professor of bioengineering and faculty member in the 91�� . “What we show here is that SOBA may be the basis of such a test.”

SOBA, which stands for soluble oligomer binding assay, exploits a unique property of the toxic oligomers. When misfolded amyloid beta proteins begin to clump into oligomers, they form a structure known as an alpha sheet. Alpha sheets are not ordinarily found in nature, and past research by Daggett’s team showed that alpha sheets tend to bind to other alpha sheets. At the heart of SOBA is a synthetic alpha sheet designed by her team that can bind to oligomers in samples of either cerebrospinal fluid or blood. The test then uses standard methods to confirm that the oligomers attached to the test surface are made up of amyloid beta proteins.

The team tested SOBA on blood samples from 310 research subjects who had previously made their blood samples and some of their medical records available for Alzheimer’s research. At the time the blood samples had been taken, the subjects were recorded as having no signs of cognitive impairment, mild cognitive impairment, Alzheimer’s disease or another form of dementia.

SOBA detected oligomers in the blood of individuals with mild cognitive impairment and moderate to severe Alzheimer’s. In 53 cases, the research subject’s diagnosis of Alzheimer’s was verified after death by autopsy — and the blood samples of 52 of them, which had been taken years before their deaths, contained toxic oligomers.

SOBA also detected oligomers in those members of the control group who, records show, later developed mild cognitive impairment. Blood samples from other individuals in the control group who remained unimpaired lacked toxic oligomers.

Daggett’s team is working with scientists at , a 91�� spinout company, to develop SOBA into a diagnostic test for oligomers. In the study, the team also showed that SOBA easily could be modified to detect toxic oligomers of another type of protein associated with Parkinson’s disease and Lewy body dementia.

“We are finding that many human diseases are associated with the accumulation of toxic oligomers that form these alpha sheet structures,” said Daggett. “Not just Alzheimer’s, but also Parkinson’s, type 2 diabetes and more. SOBA is picking up that unique alpha sheet structure, so we hope that this method can help in diagnosing and studying many other ‘protein misfolding’ diseases.”

Daggett believes the assay has further potential.

“We believe that SOBA could aid in identifying individuals at risk or incubating the disease, as well as serve as a readout of therapeutic efficacy to aid in development of early treatments for Alzheimer’s disease,” she said.

Lead author on the study is Dylan Shea, a doctoral student in the 91�� Department of Bioengineering’s Molecular Engineering Program. Co-authors are Elizabeth Colasurdo of the VA Puget Sound Health Care System; , a 91�� research assistant professor of physiology and biophysics; , a student in the 91�� Medical Scientist Training Program; Dr. , a 91�� assistant professor of neurology; Dr. , a 91�� professor of laboratory medicine and pathology; , a professor of neurosciences at the University of California, San Diego; Dr. , assistant professor of neurological surgery at the 91��; and Ge Li and Dr. , both of the 91�� Department of Psychiatry and Behavioral Sciences and the VA Puget Sound Health Care System. The research was funded by the National Institutes of Health, the Washington Research Foundation and the Northwest Mental Illness Research, Education and Clinical Center.

For more information, contact Daggett at daggett@uw.edu.

Engineering lecture series focuses on health care for the brain

91�� News staff — Mon, 10 Oct 2022 16:33:26 +0000

Injury or disease in our most complex organ — the human brain — can be hard to detect and even harder to treat. Advancing technologies for brain health requires interdisciplinary collaboration from clinicians and engineers in fields that range from data science to medicine.

This fall the 91��’s annual will feature research with potential to transform brain therapeutics from infancy to late adulthood. Two 91�� engineers will speak about their work — on detecting and treating Alzheimer’s disease as well as on developing therapies for children’s brains. These lectures are free and open to the public, and this year they will be both in person and livestreamed. .

From discovery to design: Toward early detection and treatment of Alzheimer’s disease

Valerie Daggett

The series kicks off Oct. 13, at 7:30 p.m. in Kane Hall 130 with , a professor of bioengineering. Daggett has been studying misfolded proteins that lead diseases such as Alzheimer’s, as well as Parkinson’s and others, since the 1990s. More than 5 million Americans are living with Alzheimer’s disease — a number projected to rise to 14 million by 2050 — and currently, there is no cure. Daggett’s research uses computational and experimental methods to design diagnostic and therapeutic agents to target these diseases. This work has been spun out to form with a promising platform for early diagnosis and treatment of Alzheimer’s. Hear from Daggett about the technology and collaborations driving this research.

Updated 10/28/22 – video

Engineering therapies for the pediatric brain

Elizabeth Nance

On Oct. 26, at 7:30 p.m. in Kane Hall 130, , an associate professor of chemical engineering and of bioengineering, will talk about developing therapeutics for newborn and pediatric brain disease, with the goal of improving neurological function and quality of life. Children make up 27% of the world’s population, but most therapeutics for brain disease are tested on adults. Pediatric clinical trials often follow years later. This has led to a significant gap in medical technology for infants and children. Nance’s research focuses on understanding the brain’s response to injury or disease and developing nanotherapeutic platforms to treat brain disease using nanotechnology, neurobiology and data science tools.

Updated 10/28/22 – video

Elizabeth Nance (background), and Hugo Pontes (foreground), who worked with Nance as a 91�� undergraduate student studying chemical engineering, examine thin sections of brain tissue under a microscope. Nance and Pontes were looking at how specific cells responded to a drug nanoparticle treatment to see if the treatment could reduce injury to the brain. Photo: Bryan Nakata

Synthetic peptide can inhibit toxicity, aggregation of protein in Alzheimer’s disease, researchers show

James Urton — Mon, 15 Apr 2019 19:01:59 +0000

Alzheimer’s is a disease of aggregation. Neurons in the human brain make a protein called . Such proteins on their own, called monomers of amyloid beta, perform important tasks for neurons. But in the brains of people with , amyloid beta monomers have abandoned their jobs and joined together. First, they form oligomers — small clumps of up to a dozen proteins — then longer strands and finally large deposits called plaques. For years, scientists believed that the plaques triggered the cognitive impairments characteristic of Alzheimer’s disease. But newer research implicates the smaller aggregates of amyloid beta as the toxic elements of this disease.

Now, a team led by researchers at the 91�� has developed synthetic peptides that target and inhibit those small, toxic aggregates. As they report in a published April 19 in the , their synthetic peptides — which are designed to fold into a structure known as an — can block amyloid beta aggregation at the early and most toxic stage when oligomers form.

The team showed that the synthetic alpha sheet’s blocking activity reduced amyloid beta-triggered toxicity in human neural cells grown in culture, and inhibited amyloid beta oligomers in two laboratory animal models for Alzheimer’s. These findings add evidence to the growing consensus that amyloid beta oligomers — not plaques — are the toxic agents behind Alzheimer’s disease. The results also indicate that synthetic alpha sheets could form the basis of therapeutics to clear toxic oligomers in people, according to corresponding author , a 91�� professor of and faculty member in the 91�� .

“This is about targeting a specific structure of amyloid beta formed by the toxic oligomers,” said Daggett. “What we’ve shown here is that we can design and build synthetic alpha sheets with complementary structures to inhibit aggregation and toxicity of amyloid beta, while leaving the biologically active monomers intact.”

Cellular proteins assume many different 3D structures, usually by first folding into certain types of basic shapes. The alpha sheet is a nonstandard protein structure, discovered by Daggett’s group using computational simulations. The research team has previously shown that alpha sheets are associated with aggregation of amyloid beta. These and related findings indicate that, in nature, alpha sheets likely occur in only rare instances when proteins fold incorrectly and interact in ways that disrupt cellular function, leading to so-called “” diseases like Alzheimer’s.

Ball-and-stick model of the structure of AP407, one of the synthetic alpha sheet peptides designed by the research team to inhibit toxic oligomers of amyloid beta. Photo: Shea et al., PNAS, 2019

In this new paper, Daggett and her team provide evidence that amyloid beta oligomers form an alpha sheet structure as they aggregate into longer strands and plaques. Critically, the team’s synthetic alpha sheets can actually block this aggregation by specifically binding and neutralizing the toxic oligomers.

Using both novel and conventional spectroscopic techniques, Daggett’s team observed the individual stages of development of amyloid beta clusters, from monomers to six- and 12-protein oligomers all the way up to plaques, in human neural cell lines. The researchers confirmed that the oligomer stages were most toxic to the neurons, which agrees with clinical reports of amyloid beta plaques in the brains of people who don’t have Alzheimer’s.

“Amyloid beta definitely plays a lead role in Alzheimer’s disease, but while historically attention has been on the plaques, more and more research instead indicates that amyloid beta oligomers are the toxic agents that disrupt neurons,” said Daggett.

In addition, the researchers designed and built small, synthetic alpha sheet peptides, each made up of just 23 amino acids, the building blocks of proteins. The synthetic peptides folded into a hairpin-like structure and are not toxic to cells. But the synthetic alpha sheets neutralized the amyloid beta oligomers in human neural cell cultures, inhibiting further aggregation by blocking parts of the oligomers involved in the formation of larger clumps.

The peptides also protected laboratory animals from toxic oligomer damage. In brain tissue samples from mice, the team observed an up to 82% drop in amyloid beta oligomer levels after treatment with a synthetic alpha sheet peptide. Administering a synthetic alpha sheet to living mice triggered a 40% drop in amyloid beta oligomer levels after 24 hours. In the common laboratory worm , another model for Alzheimer’s disease, treatment with synthetic alpha sheets delayed the onset of amyloid beta-induced paralysis. In addition, C. elegans worms showed signs of intestinal damage when they were fed bacteria that express amyloid beta. That damage was inhibited when the scientists first treated the bacteria with their synthetic alpha sheets.

Microscopy images of the anterior intestine of four different C. elegans worms. The gastrointestinal tracts of these worms glow green because they have been fed fluorescent bacteria. Top left: A worm fed normal bacteria. Top right: A worm fed bacteria that contain amyloid beta, which has caused intestinal damage to the worms (white arrows). Bottom left: Intestinal damage is still present if the bacteria contain both amyloid beta and a coil protein that has no effect on aggregation. Bottom right: Intestinal damage is reduced in worms fed bacteria that express amyloid beta and AP5, a synthetic alpha sheet that blocks amyloid beta oligomers. Scale bar is 10 micrometers. Photo: Shea et al., PNAS, 2019

Daggett’s team is continuing experiments with synthetic alpha sheets to engineer compounds that are even better at clearing amyloid beta oligomers. For the current study, the researchers also created a novel laboratory assay that uses a synthetic alpha sheet to measure levels of amyloid beta oligomers. They believe this assay could form the basis of a clinical test to detect toxic oligomers in people before the onset of Alzheimer’s symptoms.

“What we’re really after are potential therapeutics against amyloid beta and diagnostic measures to detect toxic oligomers in people,” said Daggett. “Those are the next steps.”

Lead author is , a 91�� doctoral student in . Co-authors are 91�� bioengineering undergraduate students , , and doctoral student Matthew Childers; and professor in the 91�� Department of Chemistry; and associate professor with the University of Colorado Boulder; and with ; and and executive director with the . The research was funded by the National Institutes of Health, the 91��, the American Microscopy Society, the National Science Foundation and the Roskamp Institute.

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For more information, contact Daggett at daggett@uw.edu.

Grant numbers: R01GMS95808, R21AG049693

New protein structure could help treat Alzheimer’s, related diseases

Michelle Ma — Mon, 28 Jul 2014 15:43:10 +0000

There is no cure for Alzheimer’s disease and other forms of dementia, but the research community is one step closer to finding treatment.

An abnormal protein, left, is intercepted by the 91��’s compound that can bind to the toxic protein and neutralize it, as shown at right. Photo: U of Washington

91�� bioengineers have designed a peptide structure that can stop the harmful changes of the body’s normal proteins into a state that’s linked to widespread diseases such as Alzheimer’s, Parkinson’s, heart disease, Type 2 diabetes and Lou Gehrig’s disease. The synthetic molecule blocks these proteins as they shift from their normal state into an abnormally folded form by targeting a toxic intermediate phase.

The discovery of a protein blocker could lead to ways to diagnose and even treat a large swath of diseases that are hard to pin down and rarely have a cure.

“If you can truly catch and neutralize the toxic version of these proteins, then you hopefully never get any further damage in the body,” said senior author , a 91�� professor of bioengineering. “What’s critical with this and what has never been done before is that a single peptide sequence will work against the toxic versions of a number of different amyloid proteins and peptides, regardless of their amino acid sequence or the normal 3-D structures.”

The were published online this month in the journal .

More than 40 illnesses known as diseases – Alzheimer’s, Parkinson’s and rheumatoid arthritis are a few – are linked to the buildup of proteins after they have transformed from their normally folded, biologically active forms to abnormally folded, grouped deposits called fibrils or plaques. This happens naturally as we age, to a certain extent – our bodies don’t break down proteins as quickly as they should, causing higher concentrations in some parts of the body.

Each amyloid disease has a unique, abnormally folded protein or peptide structure, but often such diseases are misdiagnosed because symptoms can be similar and pinpointing which protein is present usually isn’t done until after death, in an autopsy.

As a result, many dementias are broadly diagnosed as Alzheimer’s disease without definitive proof, and other diseases can go undiagnosed and untreated.

The molecular structure of an amyloid protein can be only slightly different from a normal protein and can transform to a toxic state fairly easily, which is why amyloid diseases are so prevalent. The researchers built a protein structure, called “alpha sheet,” that complements the toxic structure of amyloid proteins that they discovered in computer simulations. The alpha sheet effectively attacks the toxic middle state the protein goes through as it transitions from normal to abnormal.

In this diagram, a normal protein begins to convert into a toxic, intermediate state (above center). The 91��’s compound can bind with the toxic species and neutralize it (below center), preventing amyloid fibrils from forming. Photo: U of Washington

The structures could be tailored even further to bind specifically with the proteins in certain diseases, which could be useful for specific therapies.

The researchers hope their designed compounds could be used as diagnostics for amyloid diseases and as drugs to treat the diseases or at least slow progression.

The 91��’s designed “alpha sheet” protein structure. Photo: U of Washington

“For example, patients could have a broad first-pass test done to see if they have an amyloid disease and then drill down further to determine which proteins are present to identify the specific disease,” Daggett said.

The research team includes , Jackson Kellock and of 91�� bioengineering; and Ravi Pratap Barnwal of 91�� chemistry; Peter Law, a former 91�� graduate student; and Byron Caughey of the National Institutes of Health’s .

Working with the 91��’s , they have a patent on one compound and have submitted an application to patent the entire class of related compounds.

This research began a decade ago in Daggett’s lab when a former graduate student, Roger Armen, first discovered this new secondary structure through computer simulations. Daggett’s team was able to prove its validity in recent years by designing stable compounds and testing their ability to bind toxic versions of different amyloid proteins in the lab.

The research was funded by the National Institutes of Health (General Medicine Sciences), the National Science Foundation, the Wallace H. Coulter Foundation and Coins for Alzheimer’s Research Trust.

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