Gopal Thinakaran Archives - USF Health News https://hscweb3.hsc.usf.edu/blog/tag/gopal-thinakaran/ USF Health News Wed, 14 Dec 2022 14:44:34 +0000 en-US hourly 1 https://wordpress.org/?v=6.5.3 USF Health research team studying role that little-known protein plays in the riddle of Alzheimer’s disease https://hscweb3.hsc.usf.edu/blog/2022/12/14/usf-health-research-team-studying-role-that-little-known-protein-plays-in-the-riddle-of-alzheimers-disease/ Wed, 14 Dec 2022 14:39:02 +0000 https://hscweb3.hsc.usf.edu/?p=37527 USF Health researchers are studying how a little-known protein known as BIN1 may contribute to the formation of tangles in the brain that are a hallmark of Alzheimer’s […]

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USF Health researchers are studying how a little-known protein known as BIN1 may contribute to the formation of tangles in the brain that are a hallmark of Alzheimer’s disease, a degenerative brain condition that affects more than 6 million Americans today.

Their findings have been published in the peer-reviewed Brain: A Journal of Neurology. Leading the study was Gopal Thinakaran, PhD, CEO of the USF Health Byrd Alzheimer’s Center and Research Institute and professor of molecular medicine in the USF Health Morsani College of Medicine. Contributing to the report were Moorthi Ponnusamy, PhD, and other members of the Thinakaran Lab at the Byrd Institute.

The paper focuses on a protein called Bridging Integrator 1 – or BIN1 – a protein that is found in cells in the brain and other organs. Understanding BIN1 has been a challenge because it appears in different forms in brain cells, but breakthroughs could lead to improved therapies for people who develop Alzheimer’s as they age.

“Aging is the leading risk factor for Alzheimer’s disease,’’ Dr. Thinakaran said. “A comparison of small changes in the DNA of people worldwide with and without Alzheimer’s disease found up to 40% carry small changes in the BIN1 gene, and many of those are at a higher risk for developing the disease.’’

Until recently, other proteins, such as beta amyloid and tau, which contribute to the formation of plaques and tangles in the brain, have received more attention from researchers. But now scientists are turning to risk factors such as BIN1, believing understanding their function might offer targets for potential treatments.

BIN1 is the second-most prevalent genetic risk factor identified for late-onset Alzheimer’s disease. It encodes an adaptor protein that regulates certain functions in the brain, and evidence suggests BIN1 can alter the dynamics of cell membranes within the brain.

Thinakaran’s team looked at whether the presence of BIN1 inside the brain’s neurons favors the accumulation of tau, a toxic protein, in structures called tangles. Greater numbers of these tangles in the brain have been associated with memory loss and the death of brain cells.

The team found that laboratory mice without BIN1 in their neurons developed only milder degeneration in the regions of the brain essential for memory. Also, brain inflammation was reduced by the loss of BIN1, suggesting that BIN1 in neurons also influences nerve, or glial, cell activation during the development of Alzheimer’s disease.

“These findings mean that BIN1 in neurons promotes Alzheimer’s disease tau pathology, stimulates brain inflammation, and contributes to memory loss, thus identifying BIN1 as a possible drug target,’’ Dr. Thinakaran said.

The timing of the team’s work is critical: The number of Americans affected is expected to rise to 13 million by 2050 and cost the United States more than $1 trillion, according to the Alzheimer’s Association, a global voluntary health organization dedicated to care, support and research.

Alzheimer’s is a specific brain disease that progressively and irreversibly destroys memory and thinking skills. Eventually, Alzheimer’s disease takes away the ability to carry out even the simplest tasks.

The vast majority of people who develop Alzheimer’s dementia are age 65 or older. Experts believe this late-onset Alzheimer’s, like other common chronic diseases, develops as a result of multiple factors rather than a single cause. Although a handful of laboratories worldwide are studying how BIN1 is involved in the disease process, Thinakaran’s team is leading the research efforts to define how BIN1 acts as a risk for Alzheimer’s disease in the elderly.

Their work is funded by three major research grants totaling $7 million from the National Institute on Aging, which is part of the National Institutes of Health, along with grants from the Cure Alzheimer’s Fund and the Alzheimer’s Association.

In June, the USF Health group published a related study in the journal Molecular Neurodegeneraton, which described BIN1’s impact on glial cells, which are responsible for brain inflammation.

— Story by Kurt Loft for USF Health News 



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USF Health Alzheimer’s team publishes findings in major science journal https://hscweb3.hsc.usf.edu/blog/2022/06/16/usf-alzheimers-team-publishes-findings-in-major-science-journal/ Thu, 16 Jun 2022 21:13:18 +0000 https://hscweb3.hsc.usf.edu/?p=36589 More than 6 million Americans live with Alzheimer’s disease, and by 2050, this number is projected to rise to nearly 13 million and cost the nation more than $1 […]

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Gopal Thinakaran, PhD, in his research lab at USF Health Byrd Alzheimer’s Center.

More than 6 million Americans live with Alzheimer’s disease, and by 2050, this number is projected to rise to nearly 13 million and cost the nation more than $1 trillion.

Can anything be done to slow, or even stop, this dreaded condition? A group of USF Health researchers is taking a step closer with new research on a critical Alzheimer’s risk factor. Their work has been published by a major peer-reviewed science journal, Molecular Neurodegeneration.

The paper’s authors are part of the Thinakaran Lab, at USF Health’s Byrd Alzheimer and Research Institute. They are investigating mechanisms that may exacerbate the onset of Alzheimer’s, specifically a protein called Bridging Integrator 1, or BIN1, a critical component of inflammation. Understanding BIN1 has been a challenge because it appears in different forms.

“Brain inflammation is a big problem,’’ said Gopal Thinakaran, PhD, CEO of the Byrd Center and professor of molecular medicine at the USF Health Morsani College of Medicine. “While studying its role in different brain cells, we suspected that BIN1 might have an essential function in the brain’s immune cells, called microglia. How it influences Alzheimer’s is a fine point … it’s an important piece of the puzzle.’’

The USF Health team said BIN1 is a significant genetic risk factor for late-onset Alzheimer’s disease. BIN1 is known to regulate membrane dynamics in a range of crucial cellular processes. Although the expression of BIN1 in the brain has been characterized in detail, information regarding microglial BIN1 expression is limited. Until now, BIN1 protein expression and its role in microglia, a cell type most relevant to Alzheimer’s disease, have not been examined in depth.

The research article is titled “BIN1 is a key regulator of proinflammatory and neurodegeneration‑related activation in microglia.’’ The work is the product of a fruitful collaboration between the Thinakaran Lab at USF and the Rangaraju Lab at University of Emory. Its USF authors include Ari Sudwarts, Moorthi Ponnusamy, Shuai Wang, Mitchell Hansen, David Beaulieu‑Abdelahad, Xiaolin Zhang, Lisa Collier, Charles Szekeres, and Dr. Thinakaran.

Microglia monitor for unusual molecules in the brain generated during infection or neuronal damage. Upon detection of any hazard, microglial shape and activity get transformed from a “surveillance” to an “activated” mode, as they become competent to dispose of dead or damaged cells and unwanted proteins that clutter the brain. This brain immune response is the primary task of microglia.

Until recently, brain inflammation and the immune response of microglia were believed to be secondary to the death of neurons, which kick-start Alzheimer’s. However, studies have established that some genes specific to microglia pose the highest risk for developing Alzheimer’s disease by interfering with microglia’s activities. The USF study shows that BIN1’s involvement in disease risk may also center around its role in supporting microglial health and the brain’s immune responses.

The main message from this study is that by regulating the brain’s immune responses, BIN1 may play a crucial role in promoting microglial cell progression from the surveillance to activated microglia. In its study, the team used laboratory stains in mice. Without BIN1, microglia could not mount an appropriate response to the inflammatory challenge and remained closer to a “resting’’ state. “This means that the BIN1 function is vital for microglia to conduct surveillance in the brain for problems and be poised to mount an effective inflammatory response to tissue damage or noxious stimuli generated during brain diseases,’’ the report states.

The team is continuing its research to ask whether BIN1 may act as a risk factor for Alzheimer’s disease by changing “normal’’ brain inflammation to uncontrolled activation often found under pathological conditions.

Alzheimer’s is a specific brain disease that progressively and irreversibly destroys memory and thinking skills. Age is the biggest risk factor for the disease. Eventually, Alzheimer’s disease takes away the ability to carry out even the simplest tasks, according to the Alzheimer’s Association, a global voluntary health organization dedicated to Alzheimer’s care, support and research.

The vast majority of people who develop Alzheimer’s dementia are age 65 or older. Experts believe this late-onset Alzheimer’s, like other common chronic diseases, develops as a result of multiple factors rather than a single cause. Exceptions are cases of Alzheimer’s related to uncommon genetic changes that greatly increase risk.

However, the relatively recent discovery that Alzheimer’s begins 20 years or more before the onset of symptoms helps explain why it has been difficult to prevent and treat Alzheimer’s effectively, the association said.

Story by Kurt Loft.



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Patient commits estate gift to advance women’s heart health, skin cancer research and Alzheimer’s caregiver education at USF https://hscweb3.hsc.usf.edu/blog/2021/06/14/patient-commits-estate-gift-to-advance-womens-heart-health-skin-cancer-research-and-alzheimers-caregiver-education-at-usf/ Mon, 14 Jun 2021 12:17:08 +0000 https://hscweb3.hsc.usf.edu/?p=34246 The University of South Florida Foundation today announced a $1.8 million estate gift to USF Health that will fund a women’s heart health professorship, dermatology research endowment and […]

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The University of South Florida Foundation today announced a $1.8 million estate gift to USF Health that will fund a women’s heart health professorship, dermatology research endowment and caregiver education programs at the Byrd Alzheimer’s Center.

Community volunteer and USF Health patient Bruce Mackey made the gift in honor of his doctors Guilherme Oliveira and Basil Cherpelis.

“As a dedicated patient advocate, Bruce Mackey understands the importance of innovation to discover emerging treatments and improve quality of life,” USF President Steve Currall said. “We are grateful for his generous estate gift, which will support the work of our physician scientists to advance health, society and biomedical science in the Tampa Bay region, the state of Florida and beyond.”

An octogenarian, Mackey logs hundreds of volunteer hours annually for Moffitt Cancer Center, and he credits his vibrancy to working with people — especially patients. He tasks his doctors with the assignment of helping him keep up that pace: “I’m still running around like a 60-year-old, so let’s keep that going.”

Mr. Bruce Mackey (seated at left) joins USF Health Senior Vice President and Morsani College of Medicine Dean Dr. Charles Lockwood (seated at right) in signing a $1.8 million estate gift agreement that will support several USF Health programs, including women’s heart health/cardiology, dermatology, and Alzheimer’s caregiver education. Standing from left are Dr. Guilherme Oliveira, director of USF Health Cardiology; Dr. Basil Cherpelis, director of USF Health Mohs Surgery in Dermatology; and Dr. Gopal Thinakaran, CEO of the USF Health Byrd Alzheimer’s Center and Research Institute.

“It’s exciting to see the lasting impact Mr. Mackey is making across so many areas of medicine — cardiology, dermatology and neurology,” said Dr. Charles Lockwood, USF Health senior vice president and dean of the Morsani College of Medicine.

Mackey notes that he has lived the American dream, the grandson of immigrants who was raised in Nebraska. He and his wife, Loyce, met on a blind date, and the couple each built successful careers over the course of their 55-year marriage. Loyce conquered battles with melanoma and metastatic breast cancer, returning to her full life of social activities and tennis. Eight years after her last radiation treatments ended, a fall led to painful injuries that ultimately took her life.

In her final days, Loyce encouraged Bruce to spend the rest of his life volunteering for the cancer center that gave her the best care. He followed her wishes, relocating to Tampa Bay and serving on several patient advocacy boards and programs.

Mackey now wishes to expand his volunteer and philanthropic support to USF Health.

“Loyce and I didn’t have children, so at first we left our estate to a combination of national health organizations,” said Mackey. “But now I want to know more directly where the money is going. Giving locally to the researchers and programs at USF Health will make a greater impact.”

“We’re thrilled to help donors like Mr. Mackey build an incredible legacy through the world-class research and programs happening right here in Tampa Bay,” said USF Foundation CEO Jay Stroman. “Bruce and Loyce Mackey will be forever connected to the scientific discoveries made and the patients served through their generosity.”

Mackey’s gift will fund the Bruce E. and Loyce A. Mackey Professorship in Women’s Heart Health, which will fund a physician scientist who will lead a new women’s heart clinic at USF. “Not enough research dollars are going to women’s heart health,” said Mackey.

Since Mackey has lost family members to Alzheimer’s disease, part of his gift will also support caregiver education programs at the USF Health Byrd Alzheimer’s Center. The new fund will be used to expand workshops and support groups, create educational videos, launch a podcast series, and develop an online library of resources for caregivers of Alzheimer’s and dementia patients.

Cherpelis, a Mohs surgery expert and residency program director for USF Health Dermatology and Cutaneous Surgery, was Mackey’s first connection to USF. The Bruce E. and Loyce A. Mackey Endowed Fund for Skin Cancer Research will help fund innovations in immunostain testing and research that may lead to more accurate removal of skin tumors and other cancer cells.



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Gopal Thinakaran appointed CEO of Byrd Alzheimer’s Center & Research Institute https://hscweb3.hsc.usf.edu/blog/2021/02/22/gopal-thinakaran-named-ceo-of-byrd-alzheimers-center-research-institute/ Mon, 22 Feb 2021 16:49:11 +0000 https://hscweb3.hsc.usf.edu/?p=33484 Gopal Thinakaran, PhD, was recently appointed chief executive officer of the USF Health Byrd Alzheimer’s Center and Research Institute. Dr. Thinakaran assumed the position from Harry van Loveren, […]

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Gopal Thinakaran, PhD

USF Health’s Gopal Thinakaran, PhD, is an internationally recognized Alzheimer’s  researcher.

Gopal Thinakaran, PhD, was recently appointed chief executive officer of the USF Health Byrd Alzheimer’s Center and Research Institute. Dr. Thinakaran assumed the position from Harry van Loveren, MD, chair neurosurgery and vice dean for clinical affairs at the USF Health Morsani College of Medicine, who has chosen to step down as Byrd CEO after serving for several exemplary years in this role.

“In the past three years, the Byrd Institute has experienced tremendous growth under the leadership of Dr. van Loveren and the Neuroscience Institute Executive Committee,” Dr. Thinakaran said. “I am honored to have this opportunity to advocate for the Byrd Institute’s research, clinical, and educational missions. I will strive to attract exceptional talent to the Byrd Institute and promote a culture of excellence in basic science and clinical research.”

As the new Byrd Institute CEO, Dr. Thinakaran will work closely with the dedicated team at the Byrd Alzheimer’s Institute, including Amanda Smith, MD, director of clinical research, and Eileen Poiley, director of education.

Dr. Thinakaran, professor of molecular medicine and the Eric Pfeiffer Endowed Chair in Alzheimer’s Research at USF Health, is a permanent member on National Institutes of Health (NIH) study sections and other grant funding agencies, as well as serving on the editorial boards of several major neuroscience journals. He earned his PhD in molecular biology and genetics at the University of Guelph in Ontario, Canada. After finishing his PhD, he completed a postdoctoral fellowship in pathology from Johns Hopkins University and later served as a research associate in the Division of Neuropathology.

He joined USF Health in 2019 as a professor with tenure from the University of Chicago, where he served as a professor in the Department of Neurobiology.  Prior to that, he was an assistant professor in the Department of Pathology at the Johns Hopkins School of Medicine.

For over 20 years, Dr. Thinakaran has directed a highly collaborative research group investigating cellular and molecular mechanisms of Alzheimer’s disease pathogenesis. He has over 136 publications and has repeatedly secured research funding, including numerous NIH R01 level grants. Dr. Thinakaran brings a well-established and funded, internationally recognized research program and a wealth of leadership experience.

Under Dr. van Loveren’s leadership, the Byrd Institute, which is devoted to advancing research, education, treatment, prevention, and the early detection of Alzheimer’s disease, now has $6.7 million in federal awards, including 11 NIH RO1s and $2.8 million in clinical trials funding.

“These amounts represent very significant increases over the past four years and the upward trend is continuing, all a testament to the strength of Harry’s leadership,” said Charles J. Lockwood, MD, senior vice president for USF Health and dean of the Morsani College of Medicine. “I would like to thank Dr. van Loveren for his exceptional service to both USF Health and the Byrd Institute, and express my great confidence in Dr. Thinakaran’s leadership and his vision for the Institute moving forward.”



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BIN1 deficit impairs brain cell communication, memory consolidation https://hscweb3.hsc.usf.edu/blog/2020/03/11/bin1-deficit-impairs-brain-cell-communication-memory-consolidation/ Wed, 11 Mar 2020 14:58:15 +0000 https://hscweb3.hsc.usf.edu/?p=31011 Preclinical study by a University of South Florida Health-University of Chicago research team offers new insights into how neuronal protein BIN1 may boost Alzheimer’s disease risk TAMPA, Fla […]

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Preclinical study by a University of South Florida Health-University of Chicago research team offers new insights into how neuronal protein BIN1 may boost Alzheimer’s disease risk

TAMPA, Fla (March 11, 2020) — Bridging integrator 1, known as BIN1, is the second most common risk factor for late-onset Alzheimer’s disease, according to genome-wide studies of genetic variants. Yet, scientists know little about what this protein does in the brain.

Now a new preclinical study has discovered that a lack of BIN1 leads to a defect in the transmission of neurotransmitters that activate the brain cell communication allowing us to think, remember and behave. Led by Gopal Thinakaran, PhD, of the University of South Florida Health (USF Health) Morsani College of Medicine and colleagues at the University of Chicago, the study was published March 10 in Cell Reports.

USF Health’s Gopal Thinakaran, PhD, leads one of the few groups around the country studying BIN1 as a risk factor for late-onset Alzheimer’s disease. | Photo by Freddie Coleman

Approximately 40% of people with Alzheimer’s disease have one of three variations in the BIN1 gene – a glitch in a single DNA building block (nucleotide) that heightens their risk for the neurodegenerative disease, said the paper’s senior author Dr. Thinakaran, a professor of molecular medicine at the USF Health Byrd Alzheimer’s Center and associate dean for neuroscience research at the Morsani College of Medicine.

“Our findings 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 common risk factor for Alzheimer’s disease,” Dr. Thinakaran said. “We suspect it helps control how efficiently neurons communicate and may have a profound impact on memory consolidation – the process that transforms recent learned experiences into long-term memory.”

The research team created a mouse model in which the BIN1 gene was selectively inactivated, or knocked out, to characterize the protein’s normal function in the brain. In particular, they used advanced cell and molecular biology techniques to investigate the role of BIN1 in regulating synapses associated with learning and memory.

Peering into the brain, one synapse at a time: Electron micrograph shows selected region of a mouse brain hippocampus, the brain area responsible for learning and memory. A single synapse is marked with the yellow outline. | Image courtesy of Gopal Thinakaran, USF Health Morsani College of Medicine

To frame the study results, it helps to know that a healthy human brain contains tens of billions of brain cells (neurons) that process and transmit chemical messages (neurotransmitters) across a tiny gap between neurons called a synapse. In the Alzheimer’s disease brain, this synaptic communication is destroyed, progressively killing neurons and ultimately causing a steep decline in memory as well as other signs of dementia. Individuals most susceptible to developing full-blown Alzheimer’s in later life are those who lose the most synapses, Dr. Thinakaran said.

Among the Cell Reports study highlights:

  • Loss of BIN1 expression in neurons leads to impaired spatial learning and memory. That is, the deficit alters how effectively information about surrounding environmental space is acquired, stored, organized and used. The BIN1 knockout mice had significantly more difficulty than controls in finding the hidden platform in a Morris water maze.
  • Further analysis found that BIN1 is primarily located on neurons that send neurotransmitters across the synapse (presynaptic sites) rather than residing on those neurons that receive the neurotransmitter messages (postsynaptic sites). Synaptic transmission in the hippocampus, a brain region associated primarily with memory, showed deterioration in the release of neurotransmitters from vesicles. Vesicles are bubble-like carriers that transfer neurotransmitters from presynaptic to postsynaptic neurons.
  • The BIN1 deficiency was associated with reduced density of synapses and a decrease in the number of synaptic clusters in the knockout mice compared to controls.
  • 3-D electron microscopy reconstruction of the synapses showed a significant accumulation of docked and reserve pools of synaptic vesicles in the BIN1 knockout mice. That indicates slower (less successful) release of neurotransmitters from their vesicles, the researchers suggest.

Super-resolution imaging of BIN1 (green) combined with pre- and postsynaptic sites. White arrows at right indicate the overlap between BIN1 and synapsin, a protein involved in regulating neurotransmitter release at synapses. | Image courtesy of Gopal Thinakaran, USF Health Morsani College of Medicine, appeared first in Cell Reports (supplementary materials) doi.org/10.1016/j.celrep.2020.02.026

The study authors conclude that altogether their work highlights a non-redundant role for neuronal BIN1 in presynaptic regulation and “opens new paths for the future investigation of the precise role of BIN1 as a risk factor in Alzheimer’s disease pathophysiology.”

The research was supported by grants from the National Institutes of Health, the Cure Alzheimer’s Fund, and the Alzheimer’s Association, as well as fellowships from the BrightFocus Foundation and the Illinois Department of Public Health.

 



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Gopal Thinakaran pursues genetic clues to Alzheimer’s disease pathways https://hscweb3.hsc.usf.edu/blog/2020/02/04/gopal-thinakaran-pursues-genetic-clues-to-alzheimers-disease-pathways/ Tue, 04 Feb 2020 19:44:18 +0000 https://hscweb3.hsc.usf.edu/?p=30657 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 […]

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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



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Leading Alzheimer’s researchers join Byrd Center in August https://hscweb3.hsc.usf.edu/blog/2019/06/07/leading-alzheimers-researchers-to-join-usf-health-neuroscience-institute/ Fri, 07 Jun 2019 13:58:10 +0000 https://hscweb3.hsc.usf.edu/?p=28345 The latest neuroscientist recruits will help USF Health accelerate new discoveries in Alzheimer’s disease and other neurological disorders  Internationally recognized Alzheimer’s disease researcher Gopal Thinakaran, PhD, has been […]

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The latest neuroscientist recruits will help USF Health accelerate new discoveries in Alzheimer’s disease and other neurological disorders 

The USF Health Neuroscience Institute, home of the Johnnie B. Byrd Sr., Alzheimer’s Center, brings together scientists and physicians to investigate the complexities of the brain and its impact on human health and behavior.

Internationally recognized Alzheimer’s disease researcher Gopal Thinakaran, PhD, has been recruited by USF Health to help accelerate the interdisciplinary work of its Neuroscience Institute (NSI), home of the Johnnie B. Byrd Sr., Alzheimer’s Center. Dr. Thinakaran, a professor of neurobiology at the University of Chicago, will join USF Health on Aug. 1.

University of Chicago neurophysiologist Angèle Parent, PhD, will also arrive here Aug. 1 as an associate professor of molecular medicine and member of the Byrd Alzheimer’s Center.

“Dr. Thinakaran and Dr. Parent are outstanding additions to our growing USF Health Neuroscience Institute,” said Charles J. Lockwood, MD, senior vice president of USF Health and dean of the Morsani College of Medicine. “Building upon the success of the Byrd Alzheimer’s Center, Dr. Thinakaran will help us advance interdisciplinary research among USF Health scientists and physicians looking at the brain in unique ways to accelerate discoveries to cure a broad range of neurological disorders, including Alzheimer’s and related dementias, Parkinson’s, ataxias, epilepsy, multiple sclerosis, ALS and stroke.  Moreover, Dr. Parent brings to the USF Health NSI a critical line of research into the mechanisms of memory dysfunction in dementia”

Gopal Thinakaran, PhD

Over the last decade Dr. Thinakaran built one of the country’s leading laboratories investigating the molecular and cellular processes underlying Alzheimer’s disease, the major form of dementia afflicting an estimated 5.8 million Americans.  He uses cutting-edge cell biology techniques and mouse models to probe nerve cell pathways responsible for Alzheimer’s disease pathology and neuronal dysfunction, with the goal of finding treatments to significantly reduce or delay cognitive decline.  Recently, he began exploring the molecular link between type 2 diabetes and Alzheimer’s disease progression.

Supported by $5.5 million in National Institutes of Health (NIH) grant funding, Dr. Thinakaran’s work has implications for other age-related and chronic neurodegenerative diseases that, while diverse, share some common characteristics such as abnormal protein aggregates and excessive nerve cell death.

At USF Health, Dr. Thinakaran will assume leadership roles as associate dean for neuroscience research and NSI associate director of research, in addition to his appointments as a professor of molecular medicine and the Bagnor Endowed Chair in Alzheimer’s Research. He will work closely with NSI CEO Harry van Loveren, MD; Stephen Liggett, MD, vice dean of research for the USF Health Morsani College of Medicine; and David Kang, PhD, director of basic research at the Byrd Alzheimer’s Center, to expand and integrate basic, translational and clinical neurosciences research across USF.

Dr. Parent studies how the brain remembers and what goes wrong with memory storage mechanisms in neurodegenerative diseases, focusing on communication between nerve cells (synaptic transmission) and neuronal plasticity. This April, Dr. Parent’s team published a study in Cell Reports demonstrating that sustained amyloid precursor protein (APP) signaling favors adaptive changes in the brain and prevents memory decline in an Alzheimer’s disease mouse model. She recently received a five-year, $1.75-million NIH grant to examine how differences in APP metabolism affect memory in sleep-disturbed Alzheimer’s mice.

Angèle Parent, PhD

An accomplished scientist who does not hesitate to explore uncharted territory, Dr. Thinakaran is also “a wonderful communicator, spokesman, and builder,” Dr. Liggett said. “As USF Health intensifies its effort to conquer Alzheimer’s disease and other dementias, as well as related neuroscience research, he will play an integral role in moving us forward. His combination of excellence in these skills is not that common, and I look forward to working with him to reach new heights in these research areas.”

NSI’s Dr. Van Loveren, chair of neurosurgery at MCOM, said Dr. Thinakaran recognizes the power of bringing different disciplines together to tackle the complexities of the brain and its impact on human health and behavior. “He is a scientific leader who understands the challenges of translating laboratory findings into new therapies that can target the root causes of neurodegenerative diseases – and the value of coordinated teamwork needed to bridge that gap.”

Both Dr. Thinakaran and Dr. Parent were recruited with the help of funding allocated through USF’s designation as a Preeminent State Research University.  The University of Chicago neuroscientists are the newest NIH-funded faculty members recruited since fall 2018 to strengthen and complement existing talent at the NSI’s Byrd Alzheimer’s Center. Others include:

  • Krishna Bhat, MD, PhD, professor of molecular medicine and the Mary & Harry Goldsmith Endowed Chair in Alzheimer’s Disease, studies the genes and proteins that regulate the division of neuronal stem cells.
  • Lianchun Wang, MD, professor of molecular pharmacology and physiology and USF Endowed Chair of Neurovascular Research, investigates the structure and function of a common linear polysaccharide, heparan sulfate, in inflammation, blood vessel development, stem cell biology, cancer and Alzheimer’s disease.
  • Alexa Woo, PhD, assistant professor of molecular pharmacology and physiology, studies how multifunctional B-arrestin proteins contribute to tau pathology, a hallmark of Alzheimer’s and other neurodegenerative diseases in the brain.

Dr. Thinakaran said he was impressed by USF Health’s support of its well-established Byrd Alzheimer’s Center and the university’s drive to create an institute internationally known for its collaborative neurosciences research and training.

“I look forward to the opportunities to expand USF Health’s expertise in other neurological diseases and generate energy that will feed existing Alzheimer’s research,” he said.

 



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