The USF Health Byrd Alzheimer’s Center contributed to a new international study in Nature Medicine suggesting there is reason to reevaluate the concept of “typical” Alzheimer’s disease. The study examined the largest and most diverse population in the world to date using tau-positron emission tomography scans (tau-PET scans), an advanced neuroimaging technique.

Amanda Smith, MD, professor of psychiatry and behavioral neurosciences and clinical research director at the Byrd Alzheimer’s Center, USF Health Morsani College of Medicine, was among the Alzheimer’s Disease Neuroimaging Initiative (ADNI) coauthors for the Nature Medicine paper. As one of more than 60 ADNI sites across the U.S. and Canada, the Byrd Alzheimer’s Center shares PET and MRI images, cognitive tests, blood biomarkers and other research data used by scientists worldwide to improve the understanding of Alzheimer’s disease.

Amanda Smith, MD, is director of clinical research at the USF Health Byrd Alzheimer’s Center.

Alzheimer’s disease is characterized by toxic accumulation of the protein tau (as well as abnormal amyloid protein deposits), leading to the death of nerve cells in the brain.

The recent study, led by researchers from McGill University and Lund University, delineates four distinct patterns (subtypes) of tau pathology in Alzheimer’s disease — each distinguished by where in the brain toxic tau deposits originate and spread. The researchers showed that over time each pattern of tau accumulation correlates to different clusters of symptoms with different prognoses for the affected individuals.

For the past 30 years, many researchers have described the development of tau pathology in Alzheimer’s using a single model, despite recurring cases that do not fit that model.

The current findings help explain why different patients may develop different symptoms, Dr. Smith said.

“In the clinic where we assess hundreds of patients with Alzheimer’s disease, we know that not everyone presents with the same symptoms. Many people present with typical short-term memory loss. Some can remember but exhibit very prominent language problems. Others may have visual difficulties that cause them to not see, or to misinterpret, what is front of them,” she said. “Although advanced Alzheimer’s tends to look the same, individuals don’t necessarily fit neatly into one category (of symptoms) earlier in the disease process.”

The recent tau-PET scan findings have implications for how disease progression is staged, and ultimately helping with the discovery of individualized treatments.

Byrd neuroscientists are working to develop both anti-amyloid and anti-tau antibodies – drugs to stop or delay Alzheimer’s disease, which yet has no disease-modifying therapies. In addition to more precisely detecting the early presence of disease and monitoring its progression, the latest neuroimaging techniques help researchers see whether their investigational drugs can remove the damaging Alzheimer’s-associated proteins from the brain.

PET scans of the brains of Alzheimer’s patients, showing patterns of both amyloid and tau. CREDIT: Dean Wong, MD, PhD, Ayon Nandi, MS, and Hiroto Kuwabara, MD, PhD | Johns Hopkins Medicine

“The increasing degree of specificity provided by neuroimaging studies may advance our ability to accurately target treatments for individuals with abnormal tau in the brain – and that’s not just limited to Alzheimer’s disease,” Dr. Smith said. “While amyloid is unique to Alzheimer’s, toxic tau is found in other cognitive disorders, including certain frontotemporal dementias and chronic traumatic encephalopathy.” (CTE is brain degeneration linked to repeated head trauma, including concussions in athletes.)

Dr. Smith leads clinical trials at the USF Health Byrd Alzheimer’s Center that involve brain imaging of a wide range of older adults – from study participants with no symptoms (presymtomatic) or very minor memory difficulties, to those diagnosed with mild cognitive impairment or various stages of Alzheimer’s dementia.

Current trials include Alzheimer’s Disease Initiative 3, the AHEAD Study, and the Trial-Ready Cohort for the Prevention of Alzheimer’s Dementia (TRC-PAD).  For information on these and other clinical studies, please visit health.usf.edu/medicine/byrd/clinical-trials, or call 813-974-4904.

His team searches beyond the hallmark Alzheimer’s disease proteins for alternative treatments

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In his laboratory at the USF Health Byrd Alzheimer’s Center, neuroscientist David Kang, PhD, focuses on how different types of proteins damage the brain when they accumulate there. In the case of Alzheimer’s disease, decades of good science has zeroed in on amyloid and tau, as the two types of hallmark proteins driving the disease process that ultimately kills brain cells.

Dr. Kang and his team investigate molecular pathways leading to the formation large, sticky amyloid plaques between brain cells, and to the tau neurofibrillary tangles inside brain cells –including the interplay between the two proteins. But, he is quick to point out that amyloid and tau are “not the full story” in the quest to understand how normally aging brains go bad.

“Our goal is to understand as much of the entire Alzheimer’s disease process as possible and then target specific molecules that are either overactive or underactive, which is part of the drug discovery program we’re working on,” said Dr. Kang, professor of molecular medicine and director of basic research for the Byrd Alzheimer’s Center, which anchors the USF Health Neuroscience Institute.

Neuroscientist David Kang, PhD, (third from left)  stands with his team in his laboratory at the Byrd Alzheimer’s Center, which anchors the USF Health Neuroscience Institute.

Attacking dementia from different angles 

Dr. Kang’s group takes a multifaceted approach to studying the biological brain changes that impair thinking and memory in people with Alzheimer’s, the most common type of dementia, as well as Lewy body, vascular and frontotemporal dementias.

That includes examining how damaged mitochondria, the energy-producing power plants of the cell, contribute to pathology in all neurodegenerative diseases. “Sick mitochondria leak a lot of toxins that do widespread damage to neurons and other cells,” Dr. Kang said.

Dr. Kang’s team was the first to identify how mutations of a gene, called CHCHD10, which contributes to both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), cause both mitochondrial dysfunction and protein pathology called TDP-43. Their findings on the newly identified mitochondrial link to both neurodegenerative diseases were published in Nature Communications in 2017.

The role of selective degradation in ridding cells of abnormal proteins, old or damaged organelles (including mitochondria) and other debris is another key line of research pursued by Dr. Kang and colleagues.

A single stained nerve cell | Microscopic image courtesy of Kang lab

“We believe something more fundamental is going wrong in the brain during the aging process to tip the balance toward Alzheimer’s disease – beyond what we call proteinopathy” or deposits of malformed proteins like toxic amyloid and tau, said Dr. Kang, whose work is bolstered by nearly $8 million in grant funding from the National Institutes of Health (NIH), the Veterans Administration (VA merit awards) and the Florida Department of Health.

“I think one of the fundamental things happening is that the (cellular) plumbing system isn’t working to clear out all the accumulating junk,” he said. “That’s why we’re looking at the protective clearance mechanisms (autophagy and mitophagy) that would normally quickly remove misfolded proteins and dysfunctional mitochondria.”

Unfortunately, pharmaceutical trials to date have yielded no effective treatments for Alzheimer’s disease, the sixth leading cause of death in the U.S.  Most clinical studies have centered on developing medications to block or destroy the amyloid protein plaque formation, and a few have targeted the tau-containing neurofibrillary tangles. The five Alzheimer’s drugs currently available may provide temporary relief of symptoms, such as memory loss and confusion. But, they do not prevent or delay the mind-robbing disease as toxic proteins continue to build up and dismantle the brain’s communication network.

Lesson learned: The critical importance of intervening earlier

Some scientists argue that the “amyloid hypothesis” approach is not working. Dr. Kang is among those who maintain that amyloid plays a key role in initiating the disease process that leads to brain atrophy in Alzheimer’s – but that amyloid accumulation happens very early, as much as 10 to 20 years before people experience memory problems or other signs of dementia.

Early detection and treatment are key, Dr. Kang says, because as protein plaques and other lesions continue to accumulate in the brain, reversing the damage may not be possible.

“One reason we’ve been disappointed in the clinical trials is because so far they have primarily targeted patients who are already symptomatic,” Dr. Kang said. “Over the last decade we’ve learned that by the time someone is diagnosed with early Alzheimer’s disease, or even mild cognitive impairment, the brain has degenerated a lot. And once those nerve cells are gone they do not, for the most part, regenerate… The amyloid cascade has run its course.”

As protein plaques and other lesions continue to accumulate, becoming apparent with MRI imaging, reversing the damage may not be possible.  So, for anti-amyloid therapies – or even those targeting downstream tau – to work, patients at risk of Alzheimer’s need to be identified and treated very early, Dr. Kang said.

USF Health is recruiting healthy older adults with no signs of memory problems for a few prevention trials. A pair of Generation Program studies will test the effectiveness of investigational anti-Alzheimer’s drugs on those at high genetic risk for the disease before symptoms start. And, the NIH-sponsored Preventing Alzheimer’s with Cognitive Training (PACT) study is examining whether a specific type of computerized brain training can reduce the risk of mild cognitive impairment and dementias like Alzheimer’s disease in those age 65 and older.

To accelerate early intervention initiatives, more definitive tests are needed to pinpoint biomarkers that will predict Alzheimer’s disease development in genetically susceptible people. Dr. Kang is hopeful about the prospects.  His own team investigates how exosomes, in particular the lipid vesicles that shuttle proteins and other molecules from the brain into the circulating bloodstream, might be isolated and used to detect people at risk of proteinopathy.

“I think within the next five years, some type of diagnostic blood test will be available that can accurately identify people with early Alzheimer’s brain pathology, but not yet experiencing symptoms,” he said.

Graduate research assistant Yan Yan, a member of Dr. Kang’s research team, works at a cell culture hood.

Searching for alternative treatment targets

Meanwhile, Dr. Kang’s laboratory continues searching for other treatment targets in addition to amyloid and tau — including the enzyme SSH1, which regulates the internal infrastructure of nerve cells, called the actin cytoskeleton. SSHI, also known as slingshot, is needed for amyloid activation of cofilin, a protein identified by the USF Health neuroscientists in a recent study published in Communications Biology as a possible early culprit in the tauopathy process.

“Cofilin is overactive in the brains of Alzheimer’s patients so if we can inhibit cofilin by targeting slingshot, it may lead to a promising treatment,” Dr. Kang said.

Ultimately, as with other complex chronic diseases, Alzheimer’s may not be eliminated by a single silver-bullet cure.  Rather, Dr. Kang said, a combination of approaches will likely be needed to successfully combat the neurodegenerative disorder, which afflicts 5.8 million Americans.

“I think prevention through healthy living is definitely key, because brain aging is modifiable based on things like your diet as well as physical activity and brain exercises,” he said.  “Also, we need to focus on earlier diagnosis, before people become symptomatic, and develop next-generation drugs that can attack the disease on multiple fronts.”

Xingyu Zhao, PhD, a research associate in the Department of Molecular Medicine, is among the scientists in Dr. Kang’s laboratory studying the basic biology of the aging brain.

Fascinated by how the brain works — and malfunctions

Dr. Kang came to USF Health in 2012 after nearly 20 years as a brain researcher at the University of California San Diego, where he earned M.S. and PhD degrees in neurosciences and completed NIH National Research Service Award fellowships in the neuroplasticity of aging.

As an undergraduate Dr. Kang switched from studying engineering to a dual major in science/psychology. He began focusing on neurosciences in graduate school, he said, because tackling how the brain works and malfunctions was fascinating and always challenged him.

“With every small step forward, we learn something else about the basic biology of the aging brain,” said Dr. Kang, “It’s not just helpful in discovering what therapeutic approaches may work best against Alzheimer’s disease – we’re also learning more about other neurodegenerative conditions affecting the brain.”

In addition to leading day-to-day research operations at the Byrd Center and helping to recruit new Alzheimer’s investigators, Dr. Kang holds the Mary and Louis Fleming Endowed Chair in Alzheimer’s Research and serves as a research neurobiologist at the James A. Haley Veterans Haley Veterans’ Hospital.

He has authored more than 50 peer-reviewed journal articles on brain aging and Alzheimer’s disease research. A member of the NIH Clinical Neuroscience and Neurodegeneration Study Section since 2016, he has served on multiple national and international editorial boards, scientific panels and advisory boards.

Dr. Kang sits next to a computer monitor depicting stained microscopic images — a single neuron (far left) and the two hallmark pathological proteins for Alzheimer’s disease, tau tangles (center) and amyloid plaques (right).

Some things you may not know about Dr. Kang

• His parents were Presbyterian missionaries in Africa, so he spent nine years of his early life (third through 10^th grade) in Nigeria.
• Dr. Kang practices intermittent fasting, often forgoing breakfast and eating only within an 8-hour window. Animal studies indicate the practice may contribute to lifespan and brain health by improving cellular repair through the process of autophagy, he said. “Autophagy really kicks your cells’ plumbing system into gear to clear out all the waste.”

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

Research by Laura Blair’s team seeking to untangle tau may lead to targeted treatments for Alzheimer’s, Parkinson’s and other neurodegenerative diseases

Both of USF Health neuroscientist Laura Blair’s grandmothers died from ALS, a debilitating neurodenerative disease that progressively weakens muscles and leads to paralysis.

Laura Blair, PhD, assistant professor in the Department of Molecular Medicine, at her laboratory in the USF Health Byrd Alzheimer’s Institute

“Seeing that firsthand really put in my heart to do everything I could to help people suffering from these devastating neurodegenerative diseases,” said Blair, PhD, an assistant professor in the Morsani College of Medicine’s Department of Molecular Medicine.

As an USF undergraduate student conducting research in chemist Bill Baker’s laboratory, she had the chance to work at the USF Health Byrd Alzheimer’s Institute with Chad Dickey, PhD, an accomplished and creative NIH-funded neuroscientist who was the first to find that proteins involved in learning and memory were selectively impaired in a mouse model of Alzheimer’s disease.

Blair jumped at the opportunity.  Dr. Dickey’s National Institutes of Health (NIH) work was focusing on defects in the removal of damaged proteins from cells, with promising studies of the key role “chaperone proteins” play in regulating brain cell function in Alzheimer’s disease and other neurodegenerative disorders.

“I was excited to be part of the translational work he was doing – seeking to understand how the cell’s natural defense, these chaperone proteins, might be harnessed to regulate (abnormal) misfolding proteins in order to help fix or prevent neurodegenerative disease,” Dr. Blair said.

That was nine years ago.

Dr. Blair pulls up microscopic images of stained neurons with doctoral student Lindsey Shelton, right. The stain is used to determine if treatments administered to mice —  for instance, overexpressing cochaperone protein Aha1 or human enzyme CyP40 — change how toxic tau becomes to nerve cells.  

 Dr. Laura Blair describes the focus of her laboratory’s research.

Carrying on a scientific legacy

Since then, Dr. Blair received her doctorate in medical sciences at USF in 2014 (she also earned bachelor’s and master’s degrees here) and continued to work in Dr. Dickey’s laboratory as a postdoctoral fellow.  When Dr. Dickey passed away last year at the age 40 following a courageous battle with cancer, Dr. Blair and colleague John Koren, PhD, assumed the leadership of Dickey’s team with heavy hearts. But they push forward with their mentor’s same dedication to seeking answers and sense of urgency to “publish, publish, publish.”

“Chad was always larger than life and one of the biggest influences in my life, so losing him has been surreal,” said Blair, who keeps Dr. Dickey’s nameplate on the office she now occupies. “It’s hard, but we will continue the work he started and carry on his scientific legacy.”

“He was a tremendous mentor who taught all of us how to think about a problem and ways to come up with solutions.” And she said, smiling at the memory of Dr. Dickey’s unrelenting drive to find solutions, “he taught us there’s no sense in waiting until tomorrow for an experiment that could have been started yesterday.”

Dr. Blair with Jeremy Baker, doctoral candidate in the Department of Molecular Medicine who was the lead author for a recent PLOS Biology paper reporting that a human enzyme can reduce neurotoxic amyloids in a mouse model of dementia.

Dr. Blair’s laboratory studies how chaperone proteins drive different states of the tau protein associated with Alzheimer’s disease and more than a dozen other tauopathies, including Parkinson’s disease and traumatic brain injury.  Just as their name suggests, “chaperone” proteins escort other proteins in the cell to the places they need to be, ensure these proteins do not interact with others that could be bad influences, and see to it that proteins degrade, “or are put to bed, so to speak,” when the time is right, Dr. Blair said. Under normal circumstances, chaperone proteins help ensure tau proteins are properly folded to maintain the healthy structure of nerve cells.

Pursuing how chaperones drive different states of tau

In particular, the USF researchers explore how various chaperone proteins interact, for better or worse, with various forms of tau – ranging from soluble tau protein that can spread from one brain cell to another to the aggregated, misfolded species of tau tangles inside brain cells.  (Sticky plaques of B-amyloid protein and toxic tangles of tau protein both accumulate in patients with Alzheimer’s disease, but recent studies suggest that tau deposits may be more closely linked to the actual death of neurons leading to memory loss and dementia.)

“If we can understand which states of tau are worse in terms of driving neurotoxicity,” Dr. Blair said, “maybe we can begin to shift tau into a better state so we can help delay disease progression, if not stop it in its tracks.”

 Dr. Blair comments on differences in Alzheimer’s disease.

Dr. Blair and colleague John Koren, PhD, assistant professor (far left), co-manage a research team focusing on how chaperone proteins drive different states of the tau protein associated with Alzheimer’s disease and more than a dozen other tauopathies.

.With a support of a new five-year, $1.5-million R01 grant from the National Institute on Aging, Dr. Blair, along with co-principal investigators Paula Bickford, PhD, of the USF Center of Excellence for Aging and Brain Repair, and Vladimir Urvesky of the Department of Molecular Medicine, is looking at a family of energy-independent, small heat shock proteins known to prevent harmful tau aggregation.  In an earlier paper published several years ago in the Journal of Neuroscience, Drs. Blair, Dickey and colleagues reported that high levels of one of these chaperone proteins, Hsp27, reduced tau accumulation in neurons and rescued learning and memory in a mouse model for Alzheimer’s disease.

Dr. Blair is also principal investigator of a second, five-year $1.36-million grant from the National Institute of Mental Health (the continuation of a grant originally awarded to Dr. Dickey) to develop a treatment blocking the effect of a stress-related protein genetically linked to depression, anxiety and other behaviors associated with post-traumatic stress disorder (PTSD). The grant builds upon earlier USF research, showing that as levels of this stress-related protein, known as FKBP51, increase in the brain with age it partners with chaperone protein Hsp90 to make tau more deadly to brain cells involved in memory formation. Using a new mouse model genetically engineered to overexpress FKBP51 and exhibit symptoms like those seen in humans with PTSD, Dr. Blair’s team will test various treatments on mice exposed to early-life environmental stresses.

Dr. Blair and Shelton, lead author of a USF-led paper published this September in Proceedings of the National Academy of Sciences demonstrating that Hsp90 cochaperone Aha1 boosted production of toxic tau aggregates in a mouse model of neurodegenerative disease. 

The ultimate goal of all this tau regulation research is to discover and commercialize targeted treatments that work, whether that’s drugs that inhibit or activate chaperone proteins, or gene therapies, or a combination. Currently no FDA-approved medications for Alzheimer’s disease specifically target beta amyloid or tau; they only help improve symptoms for some patients for a limited time.

A single-bullet therapeutic approach to a disease like Alzheimer’s that affects diffuse areas of the brain is unlikely, Dr. Blair said. “The multi-treatment option is probably going to be the most effective, but it’s difficult to address that until we have individual treatments moving forward.”

“Working toward treatments to help slow and prevent these devastating neurodegenerative diseases is what keeps our laboratory so motivated and determined.”

 On working in a building that bridges research and clinical care

Slides, containing stained nerve cells from mouse brain tissue, are used by the researchers to evaluate neuronal health following various treatments.

Identifying potential treatments for neurodegenerative diseases

Building on Dr. Dickey’s work with chaperone proteins, the USF researchers continue to make significant progress in identifying potential targets to help slow or prevent neurodegenerative disease progression.

The team recently identified cochaperone protein Aha1, which binds to and stimulates the activity of heat shock protein Hsp90, as one promising therapeutic target.  Hsp90 regulates the folding, degradation and accumulation of tau. In a study published this September in  Proceedings of the National Academy of Sciences, the researchers demonstrated that Hsp90 cochaperone Aha1 boosted production of toxic tau aggregates in a mouse model of neurodegenerative disease and led to neuron loss and memory impairment.

The researchers also found that inhibiting Aha1 prevented the dramatic accumulation of tau in cultured cells. “We think Aha1 inhibitors offer promise for effects similar to Hsp90 inhibitors with less side effects,” Dr. Blair said.

Dr. Blair and Shelton work at an automated stereotactic injector station. The equipment helps the researchers determine the effects of gene therapy in the brain.

This June, in the journal PLoS Biology, Dr. Blair (principal investigator), Jeremy Baker (lead author) and colleagues reported for the first time that a naturally-occurring human enzyme – called cyclophilin 40 or CyP40 – could break apart clumps of tau in a mouse model of dementia. The USF led study found that CyP40 reduced the amount of aggregated tau, converting it into a more soluble and less toxic form of amyloid. In a mouse model of an Alzheimer’s-like disease, experimental expression of CyP40 preserved brain neurons and rescued cognitive deficits. The same enzyme also disaggregated alpha-synuclein, an aggregate associated with Parkinson’s disease.

Exactly how CyP40 can untangle clumps of tau and alpha-synuclein is not yet clear, but, Blair said “our finding suggests that CyP40, or one of the more than 40 other proteins with similar activity, may have a role to play in treating neurodegenerative diseases.”

Dr. Blair points to the hippocampus on the map of a mouse brain. An area critical for learning and memory, the hippocampus is especially vulnerable to damage at early stages of Alzheimer’s disease.

 What Dr. Blair hopes she can impart to students as a mentor

Some things you might not know about Dr. Blair:

• Blair and her husband Tom belong to a local swing dancing community, where they enjoy dancing the Lindy Hop and Balboa to ‘40s jazz.
• Blair is a mother to 7-year-old Oliver, and a stepmother to 17-year-old Laney, who is a high school senior. They also have two dogs, a Shih Tzu named Oreo and a Shih Tzu-Yorkshire terrier mix named Pumpkin.
• Participating in the Great American Teach-in two years ago, Dr. Blair spoke to her son’s kindergarten class about her career as a neuroscientist, including working on brain teaser puzzles and discussing a video of a preclinical neurobehavioral test with the young students. But, she said, the kids were particularly impressed with the squishy plastic “stress-reliever brains” she brought along.

Research associate Leo Breydo loads protein into a gel.

Cultured cells are harvested for analysis.

-Photos by Sandra C. Roa and Eric Younghans, University Communications and Marketing

The USF-led study suggests CyP40 or similar proteins may be potential therapeutics for Alzheimer’s and Parkinson’s diseases

TAMPA, Fla. (June 27, 2017) — A naturally occurring human enzyme –called cyclophilin 40 or CyP40– can unravel protein aggregates that contribute to both Alzheimer’s disease and Parkinson’s disease, reports a study led by researchers at the University of South Florida in Tampa and published today in the open access journal PLOS Biology. The finding may point toward a new therapeutic strategy for these diseases.

This is the first time that CyP40 has been shown to disaggregate, or dissolve, a toxic, soluble form of amyloid responsible for a neurodegenerative disease, according to Laura Blair, PhD, an assistant professor in the Department of Molecular Medicine at the USF Health Byrd Alzheimer’s Institute.  Blair and fellow USF researchers worked with colleagues from several institutions in Germany.

USF neuroscientist Laura Blair, PhD, principal investigator for the study, in her laboratory at the USF Health Byrd Alzheimer’s Institute.

The study found that CyP40 could reduce the amount of aggregated tau, converting it into a more soluble and less toxic form. In a mouse model of an Alzheimer’s-like disease, experimental expression of CyP40 preserved brain neurons and rescued cognitive deficits. The same enzyme also disaggregated alpha-synuclein, an aggregate associated with Parkinson’s disease.

In most neurodegenerative diseases, misfolded proteins accumulate abnormally to form an insoluble clump called amyloid. Many amyloid-forming proteins, including tau in Alzheimer’s disease and α-synuclein in Parkinson’s disease, contain the amino acid proline, which has a unique structure inducing a bend in the amino acid chain. Those bends contribute to stacking of adjacent regions of the protein promoting clumping. CyP40 may dissolve these insoluble clumps by interacting with prolines within the amyloid structure.

Exactly how CyP40 reduces aggregation is not yet clear, and the authors provide two possibilities. The enzyme may bind to aggregated protein and, by reversing the proline bend, help unstack and separate the amino acid chain. Support for this model comes from the observation that the enzyme was less effective at reducing aggregates when its action was inhibited. Alternatively, the enzyme may bind to the protein before it forms aggregates, sequestering it and thus preventing the potentially harmful clumping.

Dr. Blair with Jeremy Baker, a doctoral candidate in the Department of Molecular Medicine and a lead author on the PLOS Biology paper. Pictured on the monitor are tau oligomers.

Understanding more specifically how the enzyme works may help point toward a therapeutic strategy centered on proline’s role in amyloid formation.

“The finding that Cyp40 can untangle clumps of tau and alpha-synuclein suggests that it, or one of the more than 40 other human proteins with similar activity, may have a role to play in treating neurodegenerative disease,” Blair said.

The study was supported by grants from the National Institutes of Health, the Alzheimer’s Association and the Veterans Health Administration.

Citation:
Human cyclophilin 40 unravels neurotoxic amyloids; Jeremy D. Baker, Lindsey B. Shelton, Dali Zheng, Filippo Favretto, Bryce A. Nordhues, April Darling, Leia E. Sullivan, Zheying Sun1, Parth K. Solanki, Mackenzie D. Martin, Amirthaa Suntharalingam, Jonathan J. Sabbagh, Stefan Becker, Eckhard Mandelkow, Vladimir N. Uversky, Markus Zweckstetter, Chad A. Dickey, John Koren III, and Laura J. Blair; PLOS Biology; June 27, 2017; https://doi.org/10.1371/journal.pbio.2001336

– Photos by Eric Younghans, 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.”

David Morgan plays a leading role in an ambitious national research movement to help stop Alzheimer’s disease by 2025

In a year’s time Alzheimer’s disease affects more Americans than cancer and heart disease, the country’s top two causes of death. And, according to a report by the Rand Corporation, the total economic costs of dementia – from $159 billion to $215 billion yearly — slightly surpass those of heart disease and exceed cancer care costs by 30 percent.  Yet, the federal government spends five times more on heart disease research than on Alzheimer’s research and eight times more on cancer research.

That’s why in addition to his roles as a senior administrator and researcher, David Morgan, PhD, chief executive officer of the USF Health Byrd Alzheimer’s Institute, dedicates time advocating for more Alzheimer’s research funding at the national and state levels. Dr. Morgan, is a founding member and lead representative of the ResearchersAgainstAlzheimer’s, a coalition focusing the energies of the research community on the aggressive goal of stopping Alzheimer’s by 2025.

David Morgan, PhD

  Listen to Dr. Morgan audio clip below.

“The major risk factor for Alzheimer’s disease is old age,” said Dr. Morgan, distinguished professor of molecular pharmacology and physiology at the Morsani College of Medicine. “As we see gains in longevity, due largely to success in treating other diseases, and as more baby boomers pass age 65, the financial impact of Alzheimer’s and related dementias on Medicare will overwhelm our country’s capacity to maintain the program.”

Dr. Morgan remains optimistic that translational research conducted in the laboratories and clinics at the Institute can contribute to discoveries leading to two things by 2025:  the tools to prevent Alzheimer’s in high-risk older adults not yet showing symptoms, and treatments to effectively slow progression of the memory-robbing neurodegenerative disease in those diagnosed.

“We don’t need breakthroughs to achieve these two goals. We need the public and private resources to do the hard work of proving the science is right,” Dr. Morgan said. “Without the investment, we won’t get there.”

Leading a translational center at forefront of Alzheimer’s research and care

During Dr. Morgan’s tenure, the Byrd Alzheimer’s Institute – combining laboratory research, patient clinics, drug trials, and caregiver/health professional/first responder education under one roof — continues to grow and strengthen.

When he was tapped to lead the Institute in 2009, four doctoral researchers occupied less than 30 percent of the partially shelled, seven-floor facility.  Today, nearly 30 basic science and clinical faculty members, primarily from the Morsani College of Medicine, have appointments at the translational research center, bolstered by another dozen associate members from across USF. The building is nearly fully built out and occupied.

Under Dr. Morgan’s leadership, the USF Health Byrd Alzheimer’s Institute – a translational research center at the forefront of Alzheimer’s disease research and care — continues to grow and strengthen.

Despite intense competition for reduced research funding, Byrd Institute investigators attracted more than $7.5 million in new research grants and contracts last fiscal year, largely from the National Institutes of Health (NIH) and private foundations. New and ongoing research focuses on understanding the pathophysiology of Alzheimer’s as well as testing whether treatments targeting amyloid (plaques) or tau (tangles) in the brain can halt or slow progression of the disease itself, not just alleviate some symptoms.

“In the first six months I directed this Institute I learned more about the clinical aspects of Alzheimer’s disease than I had in the 20 preceding years,” Dr. Morgan said. “Having physicians who see patients and conduct clinical studies in the same building helps motivate scientists working in the laboratories.  It greatly facilitates the rate at which the laboratory research findings are tested in the clinic.”

Harnessing the power of advanced brain imaging techniques for clinical research

One of Dr. Morgan’s early strategic decisions was to invest in a state-of-the-art positron emission tomography (PET) scanner.  The addition has begun to pay off with a steady increase in patients referred to the Institute’s PET imaging center for brain and oncology diagnostic services. In addition, more clinical studies funded by the NIH and pharmaceutical companies are using an FDA-approved amyloid imaging agent to detect and measure amyloid, a hallmark feature of Alzheimer’s in the brain.  Scientists now know that amyloid plaques begin building up in the brain years before the first signs of memory loss.

USF is home to one of few Alzheimer’s centers in the country to own a PET scanner, which is used with neuroimaging agents in studies looking to detect signs of Alzheimer’s in the brain before symptoms are displayed. Dr. Morgan, left, with Amanda Smith, MD, the Institute’s medical director, who oversees clinical trials supported by the NIH and pharmaceutical industry.

The Institute expects to be among the 200 sites participating in the recently announced national Imaging Dementia – Evidence for Amyloid Scanning (IDEAS) study to determine the clinical usefulness of amyloid PET scans in helping doctors accurately diagnose Alzheimer’s and other dementias in cases where the cause of cognitive impairment is uncertain. Dr. Morgan is optimistic that the comprehensive study will demonstrate the value of amyloid imaging and advance Medicare and other insurance carriers toward its reimbursement.

“As we run trials evaluating drugs to see if they can reduce amyloid or tau buildup in the brain, we can monitor how much is there before and after and determine if (the investigational therapy) hit the target,” Dr. Morgan said. “It is a very important biomarker for progression of the disease.”

He looks forward to the day when physicians will be able to use advanced brain imaging techniques to screen for Alzheimer’s much like they do now for heart disease, so that intervention can be started early before cell death in the brain becomes irreversible.

Merging interests in memory and age-related brain changes to tackle Alzheimer’s

Dr. Morgan’s 35-year career in neurosciences started at Northwestern University where he did his doctoral research on the neurochemistry of learning and memory. As a postdoctoral fellow at the University of Southern California School of Gerontology in the early 1980s, he investigated age-related changes in the brains of rodents and humans. During that period momentum began building for federal efforts to combat Alzheimer’s disease and researchers discovered a new cerebrovascular protein, beta amyloid, identified as a pathological hallmark of Alzheimer’s disease and prime suspect in triggering nerve cell damage.  Dr. Morgan seized the opportunity to apply his background in aging and brain function on finding drugs to treat Alzheimer’s dementia.

Dr. Morgan worked with colleagues at USF to develop a mouse genetically modified to develop Alzheimer’s symptoms early in life. He is an expert in using transgenic mouse models to test new immune therapies against both amyloid and tau — both considered pathological hallmarks of Alzheimer’s disease.

Arriving at USF in 1992, he collaborated with colleagues to create a mouse genetically modified to develop Alzheimer’s symptoms early in life (the APP+PS1 mouse model of Alzheimer’s disease).  Dr. Morgan’s impressive research portfolio includes studies to help determine how inflammation in the brain affects the Alzheimer’s disease process and to test gene therapy and immune therapy against the amyloid peptide. He currently leads a four-year, $1.75-million R01 grant from the National Institute of Neurological Disorders and Stroke, exploring antibodies to protect against the accumulation of neuron-killing tau tangles in a transgenic mouse model.

Dr. Morgan’s work has been published in many high-impact journals including Science, Nature and the Journal of Neuroscience, and he has consulted with both major pharmaceutical companies and small biotechnology firms on the development of Alzheimer’s therapeutics.

Dr. Morgan shares laboratory space at the Institute with senior scientist Marcia Gordon, PhD, professor of molecular pharmacology and physiology; Daniel Lee, PhD, and Maj-Linda Salenica, PhD, both assistant professors of pharmaceutical sciences; and Kevin Nash, PhD, assistant professor of molecular pharmacology and physiology. While he continues to seek out new research – he and Dr. Nash are teaming up to find ways to enhance anti-inflammatory activity of the protein fractalkine in the brain — lately he spends as much time mentoring junior faculty.

“I’ve reached a point in my career where I feel it’s critically important to help junior faculty improve the grant proposals they write so they can build their own track records as principal investigators,” Dr. Morgan said.

Early in his scientific career, Dr. Morgan seized the opportunity to apply his background in aging and brain function on finding drugs to treat Alzheimer’s dementia.

Building upon scientific discoveries to find effective treatments

The search for answers about the cause of Alzheimer’s has spanned many theories in the last several decades.

“There’s a broad consensus among most researchers today that a combination of amyloid and tau is needed to cause Alzheimer’s disease.  Amyloid alone is not enough,” Dr. Morgan said. “The accumulation of amyloid outside neurons may trigger abnormal inflammation in the brain, which in turn causes tau tangles to build up inside the neurons and that leads to neuron death.”

The exact cascade of events and amount of plaques and tangles resulting in full-blown Alzheimer’s pathology is still unknown, he added, and no doubt complex.

Dr. Morgan, who holds an undergraduate degree in philosophy, is philosophical about what the USF Health Byrd Alzheimer’s Institute is working toward under his leadership.

“I’m not coming to work because I think we’re going be awarded a patent for a drug that cures Alzheimer’s disease,” he said. “But I am confident that the things we discover at USF, when integrated with the larger community of scientific knowledge, will move us closer to a better understanding of this devastating neurodegenerative disease and result in meaningful treatments to benefit patients and their families.”

In addition to his roles as senior administrator, scientist and mentor, Dr. Morgan advocates for more Alzheimer’s research funding at the national and state levels.

USF-led study suggests FKBP51 is a new treatment target for diseases with tau pathology

Tampa, FL (Sept. 3, 2013) — A stress-related protein genetically linked to depression, anxiety and other psychiatric disorders contributes to the acceleration of Alzheimer’s disease, a new study led by researchers at the University of South Florida has found.

The study is published online today in the Journal of Clinical Investigation.

Dr. Chad Dickey of the USF Health Byrd Alzheimer’s Institute was principal investigator for the study.

When the stress-related protein FKBP51 partners with another protein known as Hsp90, this formidable chaperone protein complex prevents the clearance from the brain of the toxic tau protein associated with Alzheimer’s disease.

Under normal circumstances, tau helps make up the skeleton of our brain cells.  The USF study was done using test tube experiments, mice genetically engineered to produce abnormal tau protein like that accumulated in the brains of people with Alzheimer’s disease, and post-mortem human Alzheimer’s brain tissue.

The researchers report that FKBP51 levels increase with age in the brain, and then the stress-related protein partners with Hsp90 to make tau more deadly to the brain cells involved in memory formation.

Hsp90 is a chaperone protein, which supervises the activity of tau inside nerve cells. Chaperone proteins typically help ensure that tau proteins are properly folded to maintain the healthy structure of nerve cells.

However, as FKBP51 levels rise with age, they usurp Hsp90’s beneficial effect to promote tau toxicity.

“We found that FKB51 commandeers Hsp90 to create an environment that prevents the removal of tau and makes it more toxic,” said the study’s principal investigator Chad Dickey, PhD, associate professor of molecular medicine at the USF Health Byrd Alzheimer’s Institute. “Basically, it uses Hsp90 to produce and preserve the bad tau.”

The researchers conclude that developing drugs or other ways to reduce FKB51 or block its interaction with Hsp90 may be highly effective in treating the tau pathology featured in Alzheimer’s disease, Parkinson’s disease dementia and several other disorders associated with memory loss.

A previous study by Dr. Dickey and colleagues found that a lack of FKBP51 in old mice improved resilience to depressive behavior.

The latest study was supported by a grant from the National Institute of Neurological Disorders and Stroke.

Article citation:
“Accelerated neurodegeneration through chaperone-mediated oligomerization of tau;” Laura J. Blair, Bryce A. Nordhues, Shannon E. Hill, K. Matthew Scaglione, John C. O’Leary III, Sarah N. Fontaine, Leonid Breydo, Bo Zhang, Pengfei Li, Li Wang, Carl Cotman, Henry L. Paulson, Martin Muschol, Vladimir N. Uversky, Torsten Klengel, Elisabeth B. Binder, Rakez Kayed, Todd E. Golde, Nicole Berchtold, and Chad A. Dickey; Journal of Clinical Investigation, Vol. 123, No. 10. DOI:10.1172/JCI69003.

Watch a video of Dr. Dickey explaining the role of chaperone proteins in regulating tau:

//www.youtube.com/watch?v=AuBBVreGX-k

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-USF Health-

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Media contact:
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(813) 974-3303, or abaier@health.usf.edu