Wadiche L 2013 Dr. Linda Overstreet-Wadiche, has been selected to serve as chairperson of the Neurogenesis and  Cell Fate Study Section, Center for Scientific Review at the National Institutes of Health (NIH). The NIH peer review process entails a commitment of time from the researcher and also the researcher’s home university.  It is a great honor to be considered for the position and Dr. Overstreet-Wadiche has graciously accepted the challenge.  Her term will cover July 1, 2018 – June 30, 2019.  

Dr. Overstreet-Wadiche is an associate professor in the Department of Neurobiology and a scientist at the Civitan International Research Center.

Flyer 05182018

Untangling brain neuron dysfunction in Parkinson’s
disease and dementia with Lewy bodies

Written by

volpicelli webLaura Volpicelli-Daley, Ph.D.A decay of brain function is a hallmark of Parkinson’s disease and dementia with Lewy bodies, or DLB. Specifically, cognitive dysfunction defines DLB, and nearly eight of every 10 Parkinson’s patients develop dementia.

In both of these neuro-degenerative diseases, aggregates of misfolded alpha-synuclein protein develop in brain neurons, including the hippocampus, the region of the brain that plays a vital role in the formation of memories.

These aggregates eventually lead to cell death. However, knowledge of how the abnormal aggregates affect hippocampal neuron structure and function in Parkinson’s and DLB before cell death is lacking.

Laura Volpicelli-Daley, Ph.D., assistant professor of neurology at the University of Alabama at Birmingham School of Medicine, and colleagues have now described changes in hippocampal neurons early after the pathogenic alpha-synuclein aggregates begin to appear. This understanding, combined with further exploration of the mechanisms underlying the neuronal changes, could point to novel therapeutic treatments to prevent or reverse neuronal defects and halt development of dementia.

“In Parkinson’s disease, you can give levodopa to improve motor function; but there is nothing to stop the non-motor symptoms,” Volpicelli-Daley said.

About 1 million Americans live with Parkinson’s disease, and DLB is the second-most-common form of dementia in the elderly after Alzheimer’s.

Volpicelli-Daley’s study took advantage of a novel experimental model of alpha-synuclein aggregates in neurons developed by Volpicelli-Daley and colleagues at the University of Pennsylvania eight years ago. Fibrils resembling those found in PD and DLB brains can be made by putting synthetic alpha-synuclein in a test tube and shaking the solution for several days to allow alpha-synuclein to take on a fibrillary, pathologic conformation. These fibrils can be broken up and added to neurons that are grown in culture. The nerve cells take up some of the fibrils. Inside the cells, the fibrils attract the soluble alpha-synuclein that naturally is present in the cells to form the pathological, insoluble aggregates of alpha-synuclein.

These grow to form the typical inclusions emblematic of Parkinson’s and DLB. As the pathologic alpha-synuclein inclusions continue to form, they increasingly impair neuronal excitability and connectivity, and eventually lead to neuron death.

jeremy herskowitzJeremy Herskowitz, Ph.D.In the present study, UAB researchers and a Yale University colleague looked at changes in mouse excitatory hippocampal neuronal function seven days after exposure to the fibrils, a time point before any of the neurons die. At seven days, alpha-synuclein inclusions are abundant in axons of the cells — the part of the nerve cell that sends a chemical signal to another nerve cell as part of nerve circuit functioning across the synapses between neurons. These neuronal circuits throughout the brain give rise to perception, action, thought, learning and memories.

The researchers found several significant changes in the hippocampal neurons. Formation of the pathological alpha-synuclein inclusions created multiple defects in both pre-synaptic and post-synaptic functions before neurodegeneration had begun.

“Something is clearly going on with the neurons before they die,” Volpicelli-Daley said. “There is increased activity at the presynaptic terminal, the site of the neuron that releases chemicals called neurotransmitters. On the other hand, there is decreased activity post-synaptically, the site of the neighboring neuron where these released chemicals activate messenger systems. This may suggest that there is plasticity in the neurons, that is, the neurons are adapting to the increased activity.”

“Over time, this abnormal activity may eventually lead to neuron death,” she said. “The next step will be looking at how alpha-synuclein increases presynaptic activity and whether this is a loss of alpha-synuclein function in this neuron compartment or it is caused by formation of toxic alpha-synuclein aggregates.”

“This is a groundbreaking study and one of the first to address critical and previously elusive questions regarding how toxic alpha-synuclein affects the structure and physiology of memory neurons,” said Jeremy Herskowitz, Ph.D., assistant professor in the UAB Department of Neurology and the Patsy W. and Charles A. Collat Scholar of Neuroscience.

“Our team was able to move the field forward by applying a truly multidisciplinary approach,” said Linda Overstreet-Wadiche, Ph.D., associate professor in the UAB Department of Neurobiology. “We combined anatomical, biochemical and functional assays to understand how inclusions alter neuronal function prior to cell death, and this approach yielded the unexpected finding that loss of postsynaptic structure was accompanied by enhanced presynaptic function.” 

linda wadiche 300Linda Overstreet-Wadiche, Ph.D.Volpicelli-Daley, Herskowitz and Overstreet-Wadiche are co-senior authors of the study.

In detail, they found that synaptic activity in the absence of action potentials — specifically, miniature excitatory post-synaptic potentials — increased, even though there was a major reduction in spine density on the dendrites of the neurons. Electron microscopy also showed an increased number of docked presynaptic vesicles. Spontaneous synaptic activity driven by action potentials remained normal, but there was a major impairment in spontaneous influxes of calcium ions downstream of the synapse.

The study, “α-Synuclein fibril-induced paradoxical structural and functional defects in

hippocampal neurons,” has been published in the journal Acta Neuropathologica Communications.

Other co-authors are Jessica Froula and Benjamin Henderson, UAB Department of Neurology; Jose Carlos Gonzalez, Jada Vaden, John Mclean and Gokulakrishna Banumurthy, UAB Department of Neurobiology; and Yumei Wu, Yale University School of Medicine.

Funding support came from the American Parkinson Disease Association, the Michael J. Fox Foundation and the Alzheimer’s Association, and through National Institutes of Health grants AG054719, AG043552-05, NIRG-339422, NS064025 and NS065920.


The research of David Geldmacher, MD and Erik Roberson, MD, PhD was featured on the front page of the May 2018 edition of the Birmingham Medical News. “The New War on Alzheimer’s – UAB Alzheimer’s Disease Center Advances on Multiple Fronts” highlights research currently being done in UAB’s Alzheimer’s Disease Center in conjunction with the Center for Neurodegeneration and Experimental Therapeutics (CNET).  As CNET director, Dr. Roberson works closely with Dr. Geldmacher as they work toward improving overall care of the patients. 

Birmingham Medical News is a monthly publication which features top stories in the medical field.  Visit: https://www.birminghammedicalnews.com/

UAB Alzheimer's Disease Center Advances On Multiple Fronts

Jim Freeman survived D-Day. He survived Rommel's tanks rolling over his foxhole in North Africa, and even made it home after lying wounded in the snow at the Battle of the Bulge.

He didn't want his memories to burden his family. It wasn't until he was fighting his last battle in a war he couldn't win that he began to tell his stories, hoping someone would remember. War had taken all but one of his friends. Now Alzheimer's was taking everything else.

At 19, the boy from Alabama braved machine guns on Omaha Beach to cut barbed wire and free his squad from the killing zone. Now, family dinners were frightening. An echo of the person he had been, his struggle to follow the conversation and to seem like the same Uncle Jim brought him and everyone at the table near to tears.

Dying from Alzheimer's is like falling off a cliff in slow motion. It inflicts terrible collateral damage, taking not only the life of the patient but also the lives caretakers might have lived. In an aging society where the risk of Alzheimer's doubles every five years after age 60, the financial and social impact on the nation are becoming overwhelming. To counter this threat, federal resources have been mobilized in a campaign to fight Alzheimer's on multiple fronts.

Eirk Roverson, MD, PhD

Home base for that effort in Alabama is UAB's Alzheimer's Disease Center, allied with the Center for Neurodegeneration and Experimental Therapeutics (CNET). Director Erik Roberson, MD, PhD, oversees research into the neurobiology of how Alzheimer's develops and progresses. He works closely with Clinical Core Director David Geldmacher, MD, who leads care and research teams working to improve strategies for managing Alzheimer's.

Several clinical trials are underway, testing new interventions aimed at easing symptoms and slowing progression of the disease. To assist caregivers, a new training program is now available using telemedicine. A key observational study now recruiting will follow subjects who aren't yet showing symptoms of Alzheimer's to learn more about how the disease develops, identify new targets for intervention and learn how the disease is different in the south.

"Most of what we know about Alzheimer's is based on research conducted outside the south, and a particular problem is that very few African Americans have been included in previous studies," Roberson said. "The south has high rates of diabetes, obesity, and cardiovascular disorders including hypertension--all of which have a strong association with risk for Alzheimer's Disease."

Geldmacher said, "African Americans are about twice as likely to develop Alzheimer's Disease, and they seem to respond to risk factors differently. So far, around 30 genes have been linked to the risk for developing the disease. The strongest link is to APOE4, but this gene doesn't seem to have as great an effect in African Americans. We don't know if other genes are protective or if different factors are involved. We don't understand why because we haven't had enough African Americans involved in studies."

The APOE4 gene is more common in some areas of Africa, like Nigeria, but rates of Alzheimer's are lower. This could be because obesity and diabetes rates are lower and nutrition and exercise habits are different. The UAB study will look at how these factors and others may influence the causes of the disease.

"Our goal is to recruit about 50 percent African Americans in our study so we can make a meaningful comparison of how risk factors are expressed in different gene pools," Geldmacher said. "In the past, Alzheimer's was something we diagnosed after symptoms occurred. By then, too many brain cells were damaged for us to do much to intervene. Now advances in imaging and molecular medicine allow us to see earlier changes that can begin as much as 15 years before cognitive symptoms are obvious. If we can identify ways to influence epigenetic changes and targets for pharmaceutical and other interventions, we may be able to stop or slow the damage before it happens."

Participants in the study will have imaging studies, blood and genetic testing, and optional spinal fluid collection, which will be followed by an annual evaluation to detect changes.

"With imaging, we can see the accumulation of amyloid plaques and tau tangles," Roberson said. "The extent of these changes and where they show up in the brain tends to correlate closely with the degree and type of symptoms patients experience as the disease progresses."

Much of Roberson's research is focused on learning more about the tau protein and its role in the development of tau tangles and interaction with amyloid plaques.

"Early in the disease, the presence of tau protein seems to cause hyperexcitability of brain cells which can result in subclinical seizures. If we can reduce the level of tau protein, we may be able to reduce the hyperexcitablity and prevent the damage it seems to do," Roberson said.

Risk assessment is another clinical service available through the Alzheimer's Disease Center.

"People who have a family history of Alzheimer's or other concerns can come to the clinic for a risk assessment based on genetics and their health history, and they can have imaging studies to determine whether any changes are visible," Geldmacher said. "For many, this offers the peace of mind of knowing there are no signs of the disease. If changes are present, though we have no definitive therapies yet, we can begin early work to control other health issues that seem to influence risk, such as blood sugar, obesity and hypertension.

"The risk assessment, unfortunately, isn't usually covered by insurance, which brings into play another disparity on who gets Alzheimer's. Those who can't afford an assessment are also less likely to understand the role a healthy lifestyle plays in minimizing risks.

"We're hoping that what we learn about the disease over the next few years will lead to new ways we can help everyone who is at risk."

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