Jun Tan probes the power of flavonoids in fighting Alzheimer’s disease

Backed by a diverse research team, Jun Tan, MD, PhD, often takes the road less traveled when it comes to searching for new treatments for disorders affecting both the end and beginning of the lifespan:  Alzheimer’s disease and autism.

Dr. Tan, a professor of psychiatry, holds the Robert A. Silver Endowed Chair in Developmental Neurobiology at the USF Health Morsani College of Medicine.  His translational research laboratory, based at the Silver Child Development Center, is staffed by scientists whose expertise includes molecular biology, neuroscience, clinical neurology, animal models and behavioral analysis.

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Supported by a new R21 grant from the National Institute on Aging, Dr. Jun Tan has been studying the therapeutic potential of a flavonoid found in the pulp and peel of citrus fruit (diosmin) in helping prevent and reduce Alzheimer’s disease pathology.

His knack for pursuing new approaches began in 1998, when he starting asking if Alzheimer’s disease could be linked with disorders of immunity.  This inquiry led Dr. Tan to focus on how amyloid beta (Aβ) peptide, which forms the sticky deposits in the brains of patients with Alzheimer’s, affects microglia, the resident immune cells of the brain.  He showed that Aβ activates microglia by increasing expression of a pro-inflammatory molecule, called CD40.  In addition, when microglia and nerve cells (neurons) were combined in a petri dish, treatment with Aβ caused neuronal injury by activating CD40.

It appears that when a switch (CD40) on the surface of microglia is turned “on,” these immune cells cease their usual defensive work.  They stop cleaning up the Ab protein that kills neurons. Instead, Dr. Tan explained, they begin to produce small proteins called cytokines, which damage neurons.  “Alzheimer’s disease is a trickster, able to harm and kill neurons using the brain’s own immune defenders,” Dr. Tan said.

Earlier studies by Dr. Tan and others, which generated worldwide response, established that delivering a vaccine transdermally, a method akin to a skin patch, could offer a potentially safe and effective treatment strategy for Alzheimer’s.

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Dr. Tan and his team in one of their laboratories at the USF Health Silver Child Development Center.

Most recently, Dr. Tan has been studying the therapeutic potential of a flavonoid found in the pulp and peel of citrus fruit (diosmin) in helping prevent and reduce Alzheimer’s disease pathology (plaques and tangles) and curbing inflammation in the brains of mice genetically engineered to have the symptoms of the neurodegenerative disease.

With support from a new R21 grant from the NIH’s National Institute on Aging, Dr. Tan’s group will investigate the ability of oral diosmin to reduce memory impairment and other behavioral deficits in these mice – work that may lead to clinical trials testing diosmin dietary supplements in people at highest risk for Alzheimer’s or with mild cognitive impairment.  Their work is supplemented by a grant from the Florida Department of Health’s Ed and Ethel Moore Alzheimer’s Disease Research Program.

Other recent studies by Dr. Tan demonstrated that specific autoantibodies naturally occurring in aging individuals can promote production of amyloid plaques in the brains of mice.  His team was the first to show that certain autoantibodies drive Aβ peptide formation by altering the processing of its precursor, amyloid precursor protein or APP. Findings reported last year in Cell Death & Disease laid the groundwork for understanding why the prevalence of Alzheimer’s disease increases with age and may assist with development of amyloid-specific antibodies for treatment. The results may also be useful in creating a diagnostic test for determining Alzheimer’s risk at an early age based on specific autoantibody determinations.

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Laboratory manager Huayan Hou with Dr. Tan.

“My staff are the ones who often come up with game-changing ideas and experimental approaches, driving the science,” Dr. Tan said.

For instance, Dr. Tan’s group discovered that the flavonoid EGCG, an extract of green tea, can inhibit the process that kills brain cells.  And, they recently demonstrated that the beneficial effects of EGCG may be due primarily to enhanced production of sAPPα, since restoring sAPPα levels can directly reduce the process that leads to Alzheimer’s-associated amyloid deposits (Journal of Neurochemistry, 2015).

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Dr. Tan with magnified images (20x to 40x) of Alzheimer’s disease cell models.

Recent studies have shown that young whole blood as well as human umbilical cord blood cells may help rejuvenate aging tissues.  In light of these findings, Dr. Tan’s team recently showed that young blood may benefit aging individuals by helping to reduce Ab production and the accumulation of memory-choking amyloid plaques in the brains of Alzheimer’s mice. The USF researchers reported that young blood contributes to Aβ clearance by activating a novel APP-specific enzyme called a-secretase.  (Cell Transplantation, 2015 July 30).

“Discovering the factor in young blood that enhances APP-specific a-secretase processing holds great promise for treatment of Alzheimer’s disease,” Dr. Tan said.  “The known a-secretases in the brain that cleave APP are nonspecific, so stimulating them could generate unwanted side effects. But, the APP-specific a-secretase promoting activity has great potential therapeutic benefit since its product, sAPPα, promotes nerve cell development and survival.”

Dr. Tan has brought his expertise in immunity and inflammation in the adult brain to bear on disorders of brain development affecting children.  His team found significantly increased levels of sAPPα in the blood of 60 percent of children diagnosed with autism.  Based on this study, the USF researchers developed transgenic mice overexpressing human sAPPα in the brain. Then, they used the mouse model to demonstrate that this neural growth factor’s over-production alters brain growth and immune homeostasis, and plays a key role in producing autism-like pathology and impaired behavior in the mice.  Elevated blood levels of sAPPα could also be a potential biomarker for early autism diagnosis, Dr. Tan said.

“While sAPPα is an important neuroprotective agent in adults, overproduction of sAPPα also has its detrimental effects, particularly in the developing brain,” he said.

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Brainstorming with colleagues, and critiquing each other’s ideas, is one of the key components in coming up with innovative and sound research proposals, Dr. Tan says. Here he chats with Darrell Sawmiller, PhD, senior research associate.

Over the past 20 years, Dr. Tan has authored more than 140 original scientific papers in prestigious national and international journals such as Science, Nature Neuroscience, Nature Medicine, Nature Commutations, EMBO J, PNAS, Journal of Neuroscience, Molecular Psychiatry and Acta Neuropathologica.  He has received grants and merit awards, totaling more than $13 million, from the National Institutes of Health, Veterans Administration and other peer-reviewed funding sources.

Dr. Tan’s philosophy is that everyone on his team has a strength, and the best way to lead is to combine those strengths to build a concerted effort toward success.

“Follow your dreams,” he advises the students in his laboratory.  “You can achieve great things if you believe.”

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From left, Dr. Tan with postdoctoral student Yang Xiang, PhD, and Arsan Habib, PhD student.

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Doug Shytle, PhD, (right) associate professor at the USF Center of Excellence for Aging and Brain Repair, is a co-investigator on Dr. Tan’s latest NIH grant studying the therapeutic potential of the flavonoid diosmin, found in grapefruit, oranges and other citrus, in fighting Alzheimer’s disease.

Photos by Eric Younghans, USF Health Communications and Marketing