USF Health microbiome expert Hariom Yadav, PhD, has received a grant from the National Institute on Aging to help determine if a common medication can restore microbiome diversity in older patients who have a form of heart failure and, thus, prevent the subsequent problems that tend keep these patients inactive and cause their conditions to worsen.

Hariom Yadav, PhD, was recently recruited to lead the USF Microbiome Research Center and his research focuses on the gut-brain connection (gut-brain axis) in relation to cognitive function.

Dr. Yadav, associate professor in the Division of Digestive Diseases and Nutrition for the Department of Neurosurgery and Brain Repair and Internal Medicine in the USF Health Morsani College of Medicine and director of the USF Center for Microbiome Research in the Microbiomes Institute, is a co-principal investigator and is working with co-principal investigator and project lead Dalane Kitzman, MD, at Wake Forest University in Winston-Salem, North Carolina.

The 3-year NIH consortium project research, which will include patients diagnosed with heart failure with preserved ejection fraction (HFpEF), is titled “Repurposing of Metformin for Older Patients with HFpEF.”

Preclinical studies show that gut barriers, including mucin production, are reduced in older gut and cause ‘leaky gut’, which allows certain antigens to diffuse into blood circulation, thus causing systemic inflammation. Preliminary data also suggest that older HFpEF patients have markedly reduced microbiome diversity, including reduced production of beneficial metabolites such as butyrate, which maintain health and gut wall integrity, and may help reduce leaky gut.

Metformin prescription bottle. Metformin is a generic medication name and label was created by photographer.

Metformin is a generic FDA-approved medication used for diabetes. Earlier studies, including research in Dr. Yadav’s lab, shows that metformin decreases leaky gut by improving microbial diversity and increasing intestinal wall mucin production thereby reducing systemic inflammation and improving physical function in lab model studies.

This new study seeks to translate these findings to determine if metformin improves microbiome diversity, reduces leaky gut, and reduces the inflammation associated with HFpEF in patients, a common condition in older people, particular older women.

“Earlier research suggests that metformin can inhibit a root cause of systemic inflammation – leaky gut – and its adverse consequences which are highly relevant to HFpEF, including exercise intolerance, a known barrier for HFpEF patients for staying active,” Dr. Yadav said. “We propose to test repurposing of metformin, a promising medication for improving heart failure outcomes by improving gut leakiness and microbial diversity, and that metformin will restore gut microbiome diversity and increase gut wall mucin, which in turn will reduce leaky gut and systemic inflammation and improve physical function for HFpEF patients.”

This new study is a randomized, blinded, placebo-controlled trial over 20 weeks in 80 non-diabetic HFpEF patients age 60 and older. The Wake Forest and Atrium Health team will coordinate the patients, measuring physical function, provide a quality of life questionnaire, and collect stool and blood samples. The team in Dr. Yadav’s lab will examine the samples and measure microbiome diversity and the key markers of leaky gut and of inflammation.

This study is supported by the National Institute on Aging of the National Institutes of Health under Award Number U01AG076928.

Dr. Yadav is conducting similar research associated with leaky gut and inflammation, including their connections to Alzheimer’s disease and other related dementias.

Tampa FL (June 8, 2022) – The University of South Florida received $3.2 million from the National Institute on Aging to investigate if Alzheimer’s disease can be detected early through simple blood tests.

The new funding dovetails with a $44.4 million, five-year NIH grant awarded to USF last year testing whether computerized braining training can reduce dementia risk in older adults. Called the Preventing Alzheimer’s with Cognitive Training (PACT) study, it is the largest primary prevention trial to date designed to rigorously test the effectiveness of computer-based training to protect against MCI and dementias.

Participants enrolling in the PACT study can also enroll in the study investigating whether a simple blood test can detect dementia. The PACT study will work with the National Centralized Repository for Alzheimer’s Disease and Related Dementias to analyze blood samples collected from study participants.

“We need another 2000 healthy older adults to volunteer for the PACT study. We are very grateful to the 1800 volunteers from Tampa Bay who have already joined our fight against Alzheimer’s disease by enrolling in PACT.” said principal investigator Jerri Edwards, PhD, a professor of psychiatry and behavioral neurosciences in the USF Health Morsani College of Medicine. “Participants will now not only be contributing to our work on how to possibly prevent dementia, but also advancing efforts to develop blood tests for early detection of the disease.”

Jerri Edwards, PhD, professor of psychiatry and behavioral neurosciences at the USF Health Morsani College of Medicine, is USF site principal investigator for the PACT study.

Currently, diagnosing dementia such as Alzheimer’s disease requires expensive PET scans or invasive cerebrospinal fluid samples. This new study will contribute to research working toward developing simple blood tests to improve existing methods.

Launched last year, the PACT study continues to recruit participants, seeking healthy older adults to volunteer for the landmark study examining whether computerized brain training exercises can reduce the risk of cognitive impairment and dementia such as Alzheimer’s disease. PACT study volunteers should be age 65 or older with no signs of cognitive impairment or dementia. Those accepted into the study will participate in initial testing at a PACT location at the USF Tampa or St. Petersburg campuses or at Reliance Medical in Lakeland. The PACT study is also being conducted by partner sites at Clemson University, University of Florida, University of North Florida, and Duke University.

The USF PACT study concentrates on the effectiveness of computerized programs, or brain games, for preventing dementia such as Alzheimer’s disease. These computerized training exercises are designed to potentially enhance mental quickness and visual attention. At the end of the trial, the scientists will examine the blood samples from willing participants and determine which specific blood-based biomarkers predict Alzheimer’s disease, the severity of the disease, and/or responsiveness to treatment.

The PACT study is supported by the National Institute on Aging, part of the National Institutes of Health (NIH), grant number R01AG070349. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

More information is available at the PACT study website, pactstudy.org, or by calling 813-974-6703.

University of South Florida study suggests a new approach to inhibit the buildup of brain-damaging tau tangles associated with FTLD, Alzheimer’s disease and related dementias

TAMPA, Fla. (Feb. 18, 2020) — The protein β-arrestin2 increases the accumulation of neurotoxic tau tangles, a cause of several forms of dementia, by interfering with removal of excess tau from the brain, a new study by the University of South Florida Health (USF Health) Morsani College of Medicine found.

A beta-arrestin2 oligomer (foreground) shown within a nerve cell (background). Oligomerized beta-arrestin2 plays a central role in impairing tau clearance and the development of tau aggregates (magenta) in frontotemporal lobe degeneration and Alzheimer’s disease. | Image courtesy of artist Cynthia Greco and Eric Lewandowski (beta-arrestin2 protein modeling)

The USF Health researchers discovered that a form of the protein comprised of multiple β-arrestin2 molecules, known as oligomerized β-arrestin2, disrupts the protective clearance process normally ridding cells of malformed proteins like disease-causing tau. Monomeric β-arrestin2, the protein’s single-molecule form, does not impair this cellular toxic waste disposal process known as autophagy.

Their findings were first published Feb. 18 in the Proceedings of the National Academy of Science (PNAS).

The study focused on frontotemporal lobar degeneration (FTLD), also called frontotemporal dementia — second only to Alzheimer’s disease as the leading cause of dementia. This aggressive, typically earlier onset dementia (ages 45-65) is characterized by atrophy of the front or side regions of the brain, or both. Like Alzheimer’s disease, FTLD displays an accumulation of tau, and has no specific treatment or cure.

“Our research could lead to a new strategy to block tau pathology in FTLD, Alzheimer’s disease and other related dementias, which ultimately destroys cognitive abilities such as reasoning, behavior, language, and memory,” said the paper’s lead author JungA (Alexa) Woo, PhD, an assistant professor of molecular pharmacology and physiology and an investigator at the USF Health Byrd Alzheimer’s Center.

“It has always been puzzling why the brain cannot clear accumulating tau” said Stephen B. Liggett, MD, senior author and professor of medicine and medical engineering at the USF Health Morsani College of Medicine. “It appears that an ‘incidental interaction’ between β-arrestin2 and the tau clearance mechanism occurs, leading to these dementias. β-arrestin2 itself is not harmful, but this unanticipated interplay appears to be the basis for this mystery.”

The USF Health research team included, from left: Stephen Liggett, MD, senior author; David Kang, PhD, coauthor; and JungA (Alexa) Woo, PhD, lead author. | Photo by Freddie Coleman

“This study identifies beta-arrestin2 as a key culprit in the progressive accumulation of tau in brains of dementia patients,” said coauthor David Kang, PhD, professor of molecular medicine and director of basic research for the Byrd Alzheimer’s Center. “It also clearly illustrates an innovative proof-of-concept strategy to therapeutically reduce pathological tau by specifically targeting beta-arrestin oligomerization.”

The two primary hallmarks of Alzheimer’s disease are clumps of sticky amyloid-beta (Aβ) protein fragments known as amyloid plaques and neuron-choking tangles of a protein called tau. Abnormal accumulations of both proteins are needed to drive the death of brain cells, or neurons, in Alzheimer’s, although the tau accumulations now appear to correlate better with cognitive dysfunction than Aβ, and drugs targeting Ab have been disappointing as a treatment. Aβ aggregation is absent in the FTLD brain, where the key feature of neurodegeneration appears to be excessive tau accumulation, known as tauopathy. The resulting neurofibrillary tangles — twisted fibers laden with tau — destroy synaptic communication between neurons, eventually killing the brain cells.

“Studying FTLD gave us that window to study a key feature of both types of dementias, without the confusion of any Aβ component,” Dr. Woo said.

Monomeric β-arrestin2 is mostly known for its ability to regulate receptors, molecules on the cell that are responsible for hormone and neurotransmitter signaling. β-arrestin2 can also form multiple interconnecting units, called oligomers. The function of β-arrestin2 oligomers is not well understood.

The monomeric form was the basis for the laboratory’s initial studies examining tau and its relationship with neurotransmission and receptors, “but we soon became transfixed on these oligomers of β-arrestin2,” Dr Woo said.

Neurofibrillary tangles laden with tau (stained red) destroy synaptic communication between neurons, eventually killing the brain cells. This tau pathology is a feature of frontotemporal dementia, Alzheimer’s disease and several other dementias. | Image courtesy of David Kang

Among the researchers’ findings reported in PNAS:

– Both in cells and in mice with elevated tau, β-arrestin2 levels are increased. Furthermore, when β-arrestin 2 is overexpressed, tau levels increase, suggesting a maladaptive feedback cycle that exacerbates disease-causing tau.

–  Genetically reducing β-arrestin2 lessens tauopathy, synaptic dysfunction, and the loss of nerve cells and their connections in the brain. For this experiment researchers crossed a mouse model of early tauopathy with genetically modified mice in which the β–arrestin2 gene was inactivated, or knocked out.

– Oligomerized β-arrestin2 — but not the protein’s monomeric form – increases tau.  The researchers blocked β-arrestin-2 molecules from binding together to create oligeromized forms of the protein. They demonstrated that pathogenic tau significantly decreased when β-arrestin2 oligomers are converted to monomers

– Oligomerized β-arrestin2 increases tau by impeding the ability of cargo protein p62 to help selectively degrade excess tau in the brain. In essence, this reduces the efficiency of the autophagy process needed to clear toxic tau, so tau “clogs up” the neurons.

– Blocking of β-arrestin2 oligomerization suppresses disease-causing tau in a mouse model that develops human tauopathy with signs of dementia.

Above: Control nerve cells (green), in which oligomerized beta-arrestin-2 contributes to the accumulation of disease-causing tau (magenta). Below: When the neurons are transduced with b-arrestin2 oligomerization blocking viruses, tau pathology is dramatically reduced. | Images appearing in PNAS (Fig 6D) courtesy of Alexa Woo

“We also noted that decreasing β-arrestin2 by gene therapy had no apparent side effects, but such a reduction was enough to open the tau clearance mechanism to full throttle, erasing the tau tangles like an eraser,” Dr. Liggett said. “This is something the field has been looking for — an intervention that does no harm and reverses the disease.”

“Based on our findings, the effects of inhibiting β-arrestin2 oligomerization would be expected to not only inhibit the development of new tau tangles, but also to clear existing tau accumulations due to the mechanism of enhancing tau clearance,” the paper’s authors conclude.

The work is consistent with a new treatment strategy that could be preventive for those at risk or with mild cognitive impairment, and also for those with overt dementias caused by tau, by decreasing the existing tau tangles.

The study was supported in part by grants from the National Institutes of Health, National Institute on Aging.

The USF Health neurobiologist focuses on understanding genetic risk factors that may offer new therapy targets to delay or protect against age-related cognitive decline

There has been a steep rise in the number of Americans dying of Alzheimer’s disease – up 145 percent between 2000 and 2017  The burden of this neurodegenerative disease, which relentlessly diminishes the mind, is not only borne by those living more years in a state of disability and dependence before dying, but by the family members who care for them.

No treatments exist to cure or slow the progression of Alzheimer’ disease, the major form of dementia afflicting an estimated 5.8 million Americans.

“The goal of our research is to reduce the (brain) pathology leading to Alzheimer’s disease, by identifying targeted treatments to delay the onset of disease and protect cognitive function,” said Gopal Thinakaran, PhD, professor of molecular medicine and associate dean for neuroscience research at the USF Health Morsani College of Medicine. “Finding ways to extend cognitive function so that an older person is still able to continue their daily activities or recognize a loved one – even for five more years – would greatly benefit both those suffering from Alzheimer’s and their families or other caregivers.”

Gopal Thinakaran, PhD (center), who holds the Bagnor Endowed Chair in Alzheimer’s Research, with his research team at the USF Health Byrd Alzheimer’s Center.

Dr. Thinakaran, an internationally recognized Alzheimer’s disease researcher, joined the University of South Florida from the University of Chicago in August to help accelerate the interdisciplinary work of the USF Health Neuroscience Institute. That includes recruiting a critical mass of basic scientists who can complement the university’s ongoing Alzheimer’s research while also expanding efforts to translate laboratory findings into new therapies for other neurodegenerative disorders, including Parkinson’s disease, ataxias, ALS, and multiple sclerosis.

Probing molecular, cellular changes underlying pathology

In addition to his leadership role, Dr. Thinakaran oversees a laboratory at the Byrd Alzheimer’s Center where he uses cutting-edge cell biology techniques and mouse models to study the molecular and cellular processes underlying Alzheimer’s disease. His research is supported by more than $6.1 million in grants from the National Institutes of Health (NIH), National Institute on Aging.

With normal brain aging, people experience minor lapses of memory (i.e., forgetting where their keys were left, or the name of someone just met) and some reduced speed in processing information. But disruptions in attention, memory, language, thinking and decision-making that interfere with daily life are signs of dementia.

In addition to overseeing his own laboratory research, Dr. Thinakaran holds Morsani College of Medicine leadership roles as associate dean of neuroscience research and Neuroscience Research Institute associate director of research.

Dr. Thinakaran’s lab pursues findings on relatively new genes identified through genome-wide association studies to gain insights into the mechanisms of late-onset Alzheimer’s disease, which affects people age 65 or older and accounts for the overwhelming majority of cases. Recently, the group has been investigating the role of bridging integrator 1 (BIN1), the second most common genetic risk factor for late-onset Alzheimer’s (exceeded only by APOE). Approximately 40% of people with Alzheimer’s have one of three variations in the BIN1 gene – a glitch in a single DNA building block (nucleotide) that heightens their risk for the disease, Dr. Thinakaran said.

Pursuing a common risk factor for late-onset Alzheimer’s

BIN1, expressed in all the body’s cells, has been shown to play a role in suppressing tumors and in muscle development — but little is known about what the protein does in the brain. Dr. Thinakaran was among the first to embrace the challenge of pursuing how BIN1 contributes to Alzheimer’s disease risk at a time when most researchers focused on amyloid and tau, two proteins considered the primary drivers of Alzheimer’s pathology.

Now, his team and a few others across the country probe what goes wrong in Alzheimer’s patients who carry the BIN1 risk allele. They have already confirmed that BIN1 is present both in the brain’s nerve cells (neurons) and its non-neuronal cells, such as oligodendrocytes and microglia.

Biochemist Melike Yuksel, PhD, a postdoctoral scholar in Dr. Thinakaran’s lab

A healthy human brain contains tens of billions of neurons that process and transmit chemical messages (neurotransmitters) across a tiny gap between neurons called a synapse. Alzheimer’s disease severely disrupts this synaptic communication, eventually killing cells throughout the brain and leading to a steep decline in memory and other signs of dementia.

“The single biggest correlation with cognitive decline is the loss of these synaptic communication centers between neurons,” Dr. Thinakaran said, adding that individuals most susceptible to developing full-blown Alzheimer’s in later life are those who lose the most synapses.

In a study published March 10 in Cell Reports, Dr. Thinakaran and colleagues demonstrated for the first time that the loss of BIN1 expression impaired spatial learning and memory associated with remembering where things are located. The researchers used an Alzheimer’s disease “knockout” mouse model in which neuronal BIN1 expression was inactivated in the hippocampus, a brain region involved with higher cognitive functions.

Discovering a defect in brain cell communication

A lack of BIN1 leads to a defect in the transmission of neurotransmitters needed to activate the brain cell communication that allows us to think and behave, the researchers found. Further analysis found that BIN1 was primarily located in neurons that send neurotransmitters across the synapse (presynaptic sites) rather than residing on those neurons that receive the neurotransmitter messages (postsynaptic sites). The BIN1 deficiency was also associated with reduced synapse density; a back-up of docked vesicles, the tiny bubble-like carriers that transfer neurotransmitters from presynaptic to postsynaptic neurons; and likely slower release of the neurotransmitters from their vesicles.

“Our findings so far that BIN1 localizes right at the point of (presynaptic) communication and may be precisely regulating neurotransmitter vesicle release brings us much closer to understanding how BIN1 could exert its function as a risk factor (for Alzheimer’s disease),” Dr. Thinakaran said. “We suspect it helps control how efficiently neurons communicate.”

Peering into the brain, one synapse at a time. Electron micrograph depicting selected region of a mouse brain hippocampus, the brain area responsible for learning and memory. A single synapse is marked with the yellow outline.  The human brain is estimated to have trillions of these synapses, which transmit information from one neuron to the next.| Image courtesy of Gopal Thinakaran, PhD

Antibody-stained mouse brain with Alzheimer’s disease β-amyloid deposits. The amyloid precursor proteins within healthy nerve cells and swollen neuronal processes are depicted in blue. The late-onset Alzheimer’s risk factor BIN1 is shown in green, and a marker for brain glial cells responsible for neuroinflammation is shown in magenta.| Image courtesy of Gopal Thinakaran, PhD

Dr. Thinakaran’s team also became interested in investigating whether BIN1 risk variants can interfere with the protective capacity of glia (cells supporting neurons) to mount a full inflammatory response needed to clear toxins from the brain. His USF Health group will work with researchers at Emory University to further investigate why the absence of BIN1 may impair the brain’s removal of abnormal beta-amyloid protein associated with Alzheimer’s disease.

Exploring the type 2 diabetes connection

Collaborating with a coprincipal investigator at the University of Kentucky, Dr. Thinakaran also explores the molecular link between type 2 diabetes and Alzheimer’s disease progression. An Alzheimer’s mouse model created by the Thinakaran lab allows researchers to turn on, or switch off, production of the human hormone amylin in the pancreas.

Amylin is secreted by the pancreas at higher levels, along with insulin, as diabetes begins to develop. Small amounts of this excess amylin migrate from pancreatic cells into the bloodstream and can cross the blood-brain barrier, especially in older brains where the protective barrier becomes leakier. The amylin then mixes with the brain’s beta-amyloid, which eventually builds into the sticky amyloid plaques that are a hallmark of Alzheimer’s pathology. The researchers will test in their preclinical model whether this brain amylin elevates the risk for Alzheimer’s disease, and if reducing amylin in peripheral circulation can help prevent or slow damage to cognition.

Dr. Thinakaran with biological scientist Stanislau (Stas) Smirnou

Scientists are still trying to figure out why some people remain cognitively resilient throughout life despite having neuropathology that would otherwise cause dementia. On the horizon, Dr. Thinakaran said, integrating large databases of gene expression and individual cell types will help scientists drill deeper into what specific inflammatory, metabolic and neural circuit changes shift a normally aging brain to one in which the abilities to remember, think and reason abnormally accelerate.

At the same time, data on genetics and environment/lifestyle (including diet, physical and mental exercises, sleep patterns and uncontrolled cardiovascular risk factors such as hypertension, diabetes and high cholesterol) are being collected both for patients in various stages of Alzheimer’s disease and for older adults with healthy cognitive function. “Bridging these two sets of data will be extremely valuable in understanding what confers higher risk and delineating what can keep our brains healthy as we age,” Dr. Thinakaran said.

Fascinated by a field with unprecedented challenges

Dr. Thinakaran holds a PhD in molecular biology and genetics from the University of Guelph in Canada. He completed a postdoctoral research fellowship in neuropathology and was an assistant professor of pathology at Johns Hopkins University School of Medicine. Before joining USF Health, he was a professor of neurobiology at the University of Chicago, where he built one of the country’s leading laboratories investigating pathways responsible for Alzheimer’s disease pathology and neuronal dysfunction.

Known as an accomplished scientist and thought leader who does not hesitate to tackle uncharted territory, Dr. Thinakaran studied muscle differentiation as a PhD student. But, he soon realized that muscle research had advanced to a stage where it was unlikely he could make much of an impact. At that time (early 1990s) Alzheimer’s disease research was just gaining momentum in molecular and cellular biology and posing unprecedented challenges, he said.

Biological scientist Xiaolin Zhang, MS

Once Dr. Thinakaran’s interest in Alzheimer’s was sparked during his postdoctoral training at Johns Hopkins, he seized the opportunity to pursue the emerging area of neuroscience research. “In many ways the brain and its complexity as we age is the final frontier in understanding human behavior. We’re continuing to learn every day the basics of how this organ system works, and what goes wrong when it doesn’t,” he said. “It’s a field that still has great opportunities for the next generation of young minds to make a difference.”

Dr. Thinakaran has authored more than 140 peer-reviewed publications. He is associate editor for the journals Molecular Neurodegeneration and Genes and Diseases and an editorial board member for Neurodegenerative Diseases and for Current Alzheimer Research. He serves on several scientific review/advisory committees for federal, private and public institutions. Dr. Thinakaran has received numerous awards, including the Alzheimer’s Association prestigious Zenith Fellows Award supporting senior scientists pursuing new ideas to advance Alzheimer’s and dementia research.

Some things you may not know about Dr. Thinakaran

• Dr. Thinakaran combines his artistic talents of drawing and painting with his research. Andy Warhol-like microscopic art he created won a competition and was featured as the program cover for a brain research symposium at the University of Chicago. The multicolor montage of images depicts a mouse brain section (hippocampus) stained to visualize β-secretase, an enzyme critical for generating the hallmark Alzheimer’s disease β-amyloid pathology.
• He is married to neurophysiologist Angèle Parent, PhD, associate professor of molecular medicine at the Byrd Alzheimer’s Center. They have three children: Abigaël, a freshman and aspiring neuroscientist at the University of Chicago; Daphné, 14; and Cédric, 12.
• Dr. Thinakaran enjoys cooking authentic South Indian food and other international dishes with his family.

This microscopic brain art created by Dr. Thinakaran was featured on the program cover of a University of Chicago brain research symposium.

-Video by Allison Long, and photos by Freddie Coleman, USF Health Communications and Marketing

The protein’s role in tau pathology is not well studied, but Alexa Woo seizes the opportunity to be first in discovering something new

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USF Health Alzheimer’s disease researcher JungA (Alexa) Woo, PhD, thrives on challenge.

“In terms of science especially, you face many challenges. Your experiments fail, or your hypothesis may not work out the way you expected. It takes a lot of time, effort and a passion for research to publish one paper or get that first grant,” Dr. Woo said.

“I always tell my students, ‘stay positive and be persistent.’ If you stay still, you’re going backwards. So, continue to move forward and try to find something new. Then, your research will contribute to the field and help people who suffer from these terrible diseases.”

Before earning her PhD degree in neuroscience from the University of South Florida in December 2015, Dr. Woo had already managed laboratories for senior scientists, published four papers in Nature-affiliated research journals as a first author, and given oral research presentations at the Alzheimer’s Association International Conference.  She was one of three students across USF to win the 2016 Outstanding Thesis and Dissertation Award for her work on certain molecular pathways that help drive the beta amyloid pathology contributing to Alzheimer’s disease.

Microscopic image of two nerve cells from the brain connecting| Photo courtesy of Dr. Woo

Today, Dr. Woo, an assistant professor in the USF Health Morsani College of Medicine’s Department of Molecular Pharmacology and Physiology, runs her own laboratory at the college’s Byrd Alzheimer’s Center. She was recently awarded a five-year, $1.8 million R01 grant from the National Institute on Aging at NIH to study the novel role of proteins known as beta-arrestins, or β-arrestins, in the pathology of Alzheimer’s disease and related neurodegenerative disorders. She is also the principal investigator of a $221,000 Florida Department of Health Ed and Ethel Moore Alzheimer’s Disease Research Grant investigating RanBP9 signaling in tauopathy.

Studying the role of β-arrestins in tauopathy

β-arrestins bind to and modify the function of G protein-coupled receptors (GPCRs), cell surface receptors for hormones, neurotransmitters and other substances that control virtually every cell and organ. GPCRs constitute one of the largest, most diverse protein families in the human genome; in fact, approximately a third to half of all FDA-approved drugs target these ubiquitous receptors.

“Interestingly, all the GPCRs share beta-arrestin as a common regulatory mechanism, particularly in the brain,” Dr. Woo said. “Several groups have found that β-arrestins are increased in the brains of patients with Alzheimer’s, and that they promote beta amyloid pathology.”

Neuroscientist Alexa Woo, PhD, (seated), an assistant professor of molecular pharmacology and physiology, and her research team in her laboratory at the USF Health Byrd Alzheimer’s Center. Dr. Woo’s research focuses on preventing tau proteins from malfunctioning. When tau malfunctions, it can eventually lead to neurodegenerative diseases including Alzheimer’s.

However, still unstudied is how β-arrestin regulation of GPCR activity may impact the build-up of tau proteins into neurofibrillary tangles that ultimately choke brain cells to death. This represents an important new area of research, Dr. Woo said, because tau tangles more strongly correlate with loss of memory, reasoning and other cognitive abilities than do beta amyloid plaques, the other classic hallmark of Alzheimer’s disease.

So, Dr. Woo, embraced the challenge of investigating if and how β-arrestins alter the toxic accumulation of tau protein in the brain, known tauopathy. Does this protein linked to GPCRs reduce tau aggregation, or accelerate abnormal tau aggregation?

“Based on my preliminary research, β-arrestins seem to promote tau pathology,” Dr. Woo said.  “So, if we can understand how β-arrestins affect neurodegeneration in the brain, we can modify them to mitigate the pathogenesis of Alzheimer’s disease and related dementias.”

In particular, Dr. Woo’s laboratory is trying to determine at what stage in the process of tau aggregation β-arrestins come into play.

Graduate research assistant Teresa Kee conducts experiments.

Halting the neural wreckage of destabilized microtubules

The researchers also want to figure out how β-arrestins may influence tau’s stabilization of the microtubules that structurally support billions of nerve cells in the brain. Like the railroad tracks needed for trains to move cargo from one destination to another, microtubules transport nutrients, energy-producing mitochondria and other critical materials from the body of the brain cell to distant synapses connecting these components and messages to neighboring cells.

“In Alzheimer’s disease, however, that does not happen,” Dr. Woo said.

Instead, tau clumps together disrupting the communication between nerve cells in the brain, and eventually killing the neurons, she said. Basically, when tau can no longer stabilize these essential rail tracks (microtubules), the destabilized tracks lead to a train wreck – Alzheimer’s disease.

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The key is finding new therapies to stop, or delay, Alzheimer’s disease progression in its tracks before it damages the brain beyond repair, Dr. Woo said.

“Once symptoms appear, it means you’ve already been developing Alzheimer’s disease pathology for at least 10 years. So, it’s critically important to find out how we can target pathogenic tau at an early stage – even before nerve cells begin to die.”

At the Byrd Center, basic and translational scientists work under the same roof as physicians conducting clinical research and caring for patients with Alzheimer’s and other dementias. Patients and their caregivers occasionally tour the laboratories where faculty and students update them on USF Health discoveries in Alzheimer’s disease and other neurodegenerative disorders.

“When you meet and talk to people affected by this disease, it really motivates you to learn from what’s already been done and to continue moving ahead with your research,” Dr. Woo said. “I’m hopeful that we will be able to find new treatments and, ultimately, a cure.”

Dr. Woo watches biological scientist Maria Castano work.

“Put your head down and focus on your research”

Dr. Woo received her master’s degree in biomedical science from Seoul National University in South Korea before coming to USF to pursue a PhD focused on neuroscience at the USF Health Byrd Alzheimer’s Center.

She became fascinated by the relationship between GPCRs and β-arrestins while working as a postdoctoral scholar in the laboratory of Stephen Liggett, MD, professor of internal medicine and molecular pharmacology and physiology, vice dean for research for the Morsani College of Medicine, and USF Health vice president for research. Dr. Liggett studies the genetics, molecular biology, structure and function of GPCRs and his research has provided key insights into GPCR activation, identifying many of the regulatory steps that coordinate multiple signals sent and received by all cells in the body.

“Dr. Liggett always challenged me to be my best as a scientist,” Dr. Woo said. “The first thing he said to me was ‘put your head down and focus on your research. That’s the most important thing.’”

So, she persisted — seizing every opportunity to improve her research along the way.

Two years ago Dr. Woo was recruited by MCOM as an assistant professor. Now, with her own laboratory at the Byrd Center, this junior faculty member mentors new emerging scientists, encouraging (and challenging) them to excel.

The red-orange image on the computer monitor next to Dr. Woo depicts movement of mitochondria, the powerhouses of the cell.

Some things you may not know about Dr. Woo:

• She was born and reared in Andong, South Korea, famous for its history as the Korean home of Confucian learning, which has produced many leading scholars.
• Dr. Woo originally wanted to become a South Korean military officer like her uncle. “So instead of managing a military base, now I manage my lab. Although some students may think I manage the lab like a military officer,” she said with a laugh.
• She is married to David Kang, PhD, professor of molecular medicine and director of basic research for the USF Health Byrd Alzheimer’s Institute.
• Since age 6, she has played classical piano, and still enjoys playing piano as a hobby. Her favorite composer is Chopin.

-Video and photos by Allison Long, USF Health Communications and Marketing

Researchers will focus on tau pathology in a mouse model to elucidate underlying causes.

Delirium is a serious form of mental impairment affecting 11 to 42 percent of elderly inpatients, particularly those hospitalized with infections, admitted to intensive care, or requiring surgery. The condition, marked by sudden-onset confusion and incoherence, is often underdiagnosed and can lead to devastating long-term health consequences.

Now, researchers at the University of South Florida have been awarded a five-year, $3.48 million grant from the National Institute on Aging (NIA) to investigate the observation that older adults who experience delirium while hospitalized can have higher risk afterwards of developing dementia.  They will also attempt to explain why the condition accelerates decline in patients who already have dementia.

The award titled “Influence of systemic immune inflammation upon the tauopathy phenotype in mouse models” will focus on tao pathology in a mouse model. Tau is one of the proteins that accumulates in Alzheimer’s brain tissue and is thought to cause the death of neurons. The grant was in response to a specific request from NIA for proposals forged by interdisciplinary investigative teams to address this question.

“The ultimate goal of this project is to identify the factors associated with general illness that impact Alzheimer’s pathology in the brain and block the influence of those factors on tau pathology, thus decreasing the risk or progression of dementia in individuals who develop general illnesses.” said principal investigator David Morgan, PhD, CEO of the USF Health Byrd Alzheimer’s Institute.

Dr. David Morgan.

“It is testimony to the breadth of expertise at USF that we were able to assemble this team of experts to tackle this very complex problem and compete successfully with other universities.”

Joining Dr. Morgan on the study are co-investigators from the USF Health Morsani College of Medicine and the USF College of Pharmacy: Paula Bickford, PhD, professor at the USF Center of Excellence for Aging and Brain Repair; Chuanhai Cao, PhD, associate professor of pharmaceutical science; Marcia Gordon, PhD, professor of molecular pharmacology and physiology; Daniel Lee, PhD, assistant professor of pharmaceutical science; Kevin Nash, PhD, assistant professor of molecular pharmacology and physiology; Maj-Linda Selenica, PhD, assistant professor of pharmaceutical science; and Ken Ugen, PhD, professor of molecular medicine.

This investigative team combines expertise in Alzheimer’s disease, aging brain function, innate immunity and adaptive immunology to unravel the mechanisms by which general illness can increase risk and progression of dementia.

The researchers suspect that hospitalization and immune activation may feed back onto the brain to speed up Alzheimer’s pathology, Dr. Morgan said. “However, like all epidemiology, it could be reverse causality.  That is, those with existing Alzheimer’s pathology may be more prone to delirium with major infectious illness.  The studies we do in mice will help determine what the direction is.”

The director of the National Institutes of Health’s National Institute on Aging yesterday visited the USF Health Byrd Alzheimer’s Institute, the state’s only freestanding Alzheimer’s center offering clinical assessment, laboratory research, education and care under one roof.

NIA Director Richard Hodes, MD, introduced by U.S. Rep. Kathy Castor and Byrd Alzheimer’s Institute CEO David Morgan, PhD, spoke about the NIA’s initiatives to build momentum in the fight against Alzheimer’s disease.   He also met with NIA-funded researchers from across USF and toured the Byrd Institute’s Center for Memory CARE.

Dr. Richard Hodes (left), director of the National Institute on Aging, and Dr. David Morgan, CEO of the USF Health Byrd Alzheimer’s Institute, listen as a faculty member explains his research project.

The NIA supports biomedical, clinical, behavioral, and social research related to the aging process, healthy aging, and age-related diseases and disabilities.  It is the primary federal agency funding and conducting Alzheimer’s disease research.

NIA-funded research at USF is approximately $3.5 million yearly, and  60 percent of the Byrd Alzheimer’s Institute funding is from NIA, Dr. Morgan said.

While working to understand the basic mechanisms of normal and abnormal aging, and to discover new treatments, prevention, and a cure for Alzheimer’s disease, Dr. Hodes said, the NIA also has a responsibility speed the translation of existing knowledge into practical therapies and public information.  The NIA also funds research to improve the quality of life for patients with Alzheimer’s disease and their caregivers.

Dr. Hodes outlined research advances since the first genes linked to an increased risk of Alzheimer’s disease were identified in the early 1990s.  These have included the development of mice genetically modified to exhibit the brain pathology of Alzheimer’s disease, genome-wide studies driving an integrated systems approach to find genes and networks that distinguish a brain affected by Alzheimer’s disease, and the identification of biomarkers to help with earlier detection and track disease progression.

L to R: Dr. Amanda Smith, medical director of the USF Health Byrd Alzheimer’s Institute, Institute CEO Dr. David Morgan: NIA Director Dr. Richard Hodes; U.S. Rep Kathy Castor, Institute Chief Scientific Officer Dr. Edwin Weeber, and Institute Associate Director Dr. Jessica Banko.

Most recently, revolutionary advances in imaging have allowed researchers to visualize nerve-killing Alzheimer’s amyloid proteins in the brain years before symptoms such as memory loss first appear. This innovative technology “gives us the ability to do clinical studies we could not do in the past,” Dr. Hodes said.

For example, he cited a new NIA randomized controlled clinical trial that will involve people at high risk for early-onset Alzheimer’s disease and test whether an immune therapy helps prevent amyloid accumulation or facilitates its clearance from the brain in these genetically-predisposed individuals.   Using imaging technology, investigators will track amyloid lesions in the brains of study participants who receive the investigational amyloid antibody and those who don’t.

“Over time they can see whether the treatment makes a difference or not,” Dr. Hodes said. “The goal is to find a way to intervene (early) before irreparable damage is done to the brain.”

Institute team members, including Director of Education Eileen Poiley (far left), led Dr. Hodes on a tour of the Center for Memory CARE.  Here they pause at the family room/kitchen area designed for the comfort and convenience of patients and caregivers.

Another emerging area of study for NIA is looking at how genes may interact with the environmental and behavioral factors to influence age-related cognitive decline.

Following his formal talk, Dr. Hodes met with about 20 USF faculty members supported by the NIA to learn more about their areas of study.   Their work includes such research as investigating the link between hearing and cognition; evaluating electrophysiological biomarkers for early-onset cognitive decline; testing nutritional approaches, like blueberries and spirulina, for protection against neural cell degeneration; searching for drugs or gene therapy to manipulate the chaperone proteins that regulate the fate of a hallmark Alzheimer protein known as tau; examining the role that the protein reelin plays in regulating and changing nerve cell connections in the region of the brain where new memories are formed; exploring cell-based therapies for Alzheimer’s disease; and using visual and auditory cues to help people with dementia remember better.

USF President Judy Genshaft greets Dr. Hodes.

Dr. Hodes was impressed by breadth and strength of  USF’s interdisciplinary aging research and recognized the distinctiveness of the Byrd Institute’s Center for Memory CARE, a one-stop multispecialty memory care center especially designed for Alzheimer’s patients and caregivers, Dr. Morgan said.  USF President Judy Genshaft and Stephen Klasko, MD, outgoing senior vice president of USF Health and medical school dean, accompanied Dr. Hodes on his tour of the facility.

USF faculty members whose research is supported by NIA met with Dr. Hodes to share the scope of their work.

Dr. Marcia Gordon (left), professor of molecular pharmacology and physiology, and Dr. Meredeth Rowe, professor of nursing, are among the NIA-supported faculty members at USF.

Dr. Hodes gets a look at the control room for the Institute’s onsite CT/PET scanner, which helps diagnose dementia and support drug discovery.

Dr. Hodes chats with Dr. Stephen Klasko, outgoing senior vice president of USF Health and medical school dean.

Dr. Hodes, a leading immunologist, has directed the National Institute on Aging since 1993 and devoted his tenure to developing a strong, diverse and balanced research program.

 Photos by Eric Younghans, USF Health Communications