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.

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.

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.

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).

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.

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.”

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

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

Tampa, Fla. (April 10,  2012) – A research team led by the University of South Florida’s Department of Psychiatry & Behavioral Neurosciences has found that a fragment of the amyloid precursor protein (APP) — known as sAPP-α and associated with Alzheimer’s disease — appears to regulate its own production.  The finding may lead to ways to prevent or treat Alzheimer’s disease by controlling the regulation of APP.

Their preclinical study is published online today in Nature Communications.

“The purpose of this study was to help better understand why, in most cases of Alzheimer’s disease, the processing of APP becomes deregulated, which leads to the formation of protein deposits and neuron loss,” said study senior author Dr. Jun Tan, professor of psychiatry and the Robert A. Silver Chair, Rashid Laboratory for Developmental Neurobiology at the USF Silver Child Development Center.   “The many risk factors for Alzheimer’s disease can change the way APP is processed, and these changes appear to promote plaque formation and neuron loss.”

Microscopic image showing the merging of the amyloid precursor protein fragment,
sAPP-α, and the APP-converting enzyme BACE 1, in neuronal cells.  This co-localization
suggests that sAPP-α may serve as the body’s mechanism to inhibit BACE1  activity and
thus lower production of the toxic amyloid beta characteristic of Alzheimer’s disease.

An estimated 30 million people worldwide and 5 million in the U.S. have Alzheimer’s.  With the aging of the “Baby Boom” generation, the prevalence of the debilitating disease is expected to increase dramatically in the U.S. in the coming years.  Currently, there are no disease-modifying treatments to prevent, reverse or halt the progression of Alzheimer’s disease, only medications that may improve symptoms for a short time.

“For the first time, we have direct evidence that a secreted portion of APP itself, so called ‘ sAPP-α,’ acts as an essential stop-gap mechanism,” said the study’s lead author Dr. Demian Obregon, a resident specializing in research in the Department of Psychiatry & Behavioral Neurosciences at USF Health. “Risk factors associated with Alzheimer’s disease lead to a decline in sAPP-α levels, which results in excessive activity of a key enzyme in Aβ formation.”

Dr. Demian Obregon is one of the study's coauthors.

In initial studies using cells, and in follow-up studies using mice genetically engineered to mimic Alzheimer’s disease, the investigators found that the neutralization of sAPP-α leads to enhanced Aβ formation.  This activity depended on  sAPP-α’s ability to associate with the APP-converting enzyme, BACE1.  When this interaction was blocked,  Aβ formation was restored.

The authors suggest that through monitoring and correcting low sAPP-α levels, or through enhancing its association with BACE, Alzheimer’s disease may be prevented or treated.

Dr. Demian Obregon and Dr. Lucy Hou of the USF Department of Psychiatry and Behavioral Neurosciences, the study’s lead authors, collaborated with colleagues from the Laboratory of Neurosciences at the National Institute on Aging and colleagues at the USF Center for Aging and Brain Repair, the James A. Haley Veterans’ Hospital and Saitama Medical University in Japan.  Other study authors included: Juan Deng, MD, Brian Giunta, MD, Jun Tian, BS, Donna Darlington, MS, Md Shahaduzzaman, MD, Yuyuan Zhu, MD, PhD, Takashi Mori, DVM, PhD, and Mark P. Mattson, PhD.

The research was supported by a grant from the National Institutes of Health, National Institute on Aging, and a Veterans Affairs Merit grant.

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Media contact:
Anne DeLotto Baier, USF Health Communications, abaier@health.usf.edu or (813) 974-3300