Jose F. AbisambraJose F. Abisambra, Ph.D.
Assistant Professor of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, recipient of a 2012 New Investigator Research Grant to Promote Diversity and a 2014 New Investigator Research Grant.

Dr. Jose Abisambra is exploring how a protein involved in normal brain function exerts toxic effects when damaged that could lead to Alzheimer’s disease or related dementia.

Research focus

Tau, a protein that is present in our brains, helps maintain the proper function of brain cells called neurons. For example, since neurons are elongated cells, molecular “cargo” must be transported carefully along the neuron’s extensions to the far-reaching limits of the cell. Tau stabilizes protein bridges (microtubules) that help promote the transport of cargo across the cell. Since the inside of neurons is dynamic and crowded, microtubules must disassemble once the cargo is successfully transported. For this to occur, phosphate molecules are added to tau so that the protein can detach itself from the microtubule. However, detached tau is highly unstable, and if not regulated properly, it can adopt an abnormal shape that results in toxicity. For example, if too much phosphate is added to tau (a process called “hyperphosphorylation”), tau proteins clump together into harmful structures called neurofibrillary tangles. Such tangles hinder cell-to-cell communication in the brain and lead to brain cell death in Alzheimer’s. Yet, the exact biological mechanisms that underlie tau’s toxicity remain unknown. Dr. Jose Abisambra is working to overcome these gaps in our knowledge. His studies are shedding new light on how abnormal tau may disrupt brain cell function and advance the progression of brain disease, such as Alzheimer’s disease and related dementias.

Can toxic tau subvert the cellular “factories” in our brains?

Dr. Abisambra received two research grants from the Alzheimer’s Association. Both grants have funded studies on how abnormal tau can prevent brain cells from making the proteins that are vital to their health and proper function. Tau appears to hinder the protein-making “factories” in nerve cells — factories that involve a group of cellular compartments called the endoplasmic reticulum (or ER) and cellular structures known as ribosomes. For their first grant, a 2012 New Investigator Research Grant to Promote Diversity, Dr. Abisambra and his team used mice that were genetically engineered to develop abnormal tau. They found that this tau activated a stress response in the animals’ endoplasmic reticulum. Moreover, the tau-induced stress hindered ER function in the mice, placing their brain cells at risk of deterioration and death.

The results of this effort led, in 2014, to a second study funded by the Alzheimer’s Association. Dr. Abisambra now focused on how tau affects ribosomes. In preliminary experiments, Abisambra and his team had observed that hyperphosphorylated tau can bind to ribosomes in nerve cells and disrupt ribosomal activity. The goal of their 2014 project was to learn whether abnormal tau could inhibit ribosomes from making new proteins. Using autopsied brain samples from people who had Alzheimer’s disease, the investigators found that abnormal tau does indeed impair the ribosomes’ protein-making function. This finding suggests an important mechanism by which tau-related diseases, or tauopathies, begin in the brain and lead to Alzheimer’s and other brain disorders. It also suggests a novel target for potential disease therapies. These exciting results were published in 2016 in The Journal of Neuroscience.

A scientific family

Dr. Abisambra’s interest in science began early, and it was encouraged by many loving relatives. As he says, “My parents fostered my scientific curiosity. When I was 10, my grandfather Miguel gave me a toy microscope with a booklet on how to study microorganisms. He was a chemical engineer and was very passionate about science and research, but most of all he encouraged me to love to learn.” Abisambra’s other grandfather, a well-known psychiatrist, instilled in him a passion for studying the brain. This passion was intensified several years later when Miguel had a stroke. “The peculiar outcome of the stroke on my grandfather’s speech and other cognitive faculties showed me the fragility of the brain and taught me the complexity of synaptic connections (or the ability of brain cells to send and receive chemical messages through channels called synapses). But most importantly, the impact (that) his cognitive decline had on our lives has fueled my desire to understand how the brain works to prevent and treat disease.” All of these early experiences have led to the breakthroughs that Abisambra is now making in tauopathy research.

Impact of Association funding
Dr. Abisambra began his relationship with the Alzheimer’s Association in 2009, when he volunteered at the Alzheimer’s Association International Conference (or AAIC). Since then, this relationship has had a powerful impact on his scientific career. Dr. Abisambra credits his 2012 grant as a major factor in securing his current faculty position at the University of Kentucky. The grant also helped him earn several important research awards, including an R01 Research Project Grant from the National Institutes of Health (NIH) and an FY15 Peer Reviewed Alzheimer’s Research Program (PRARP) award from the U.S. Department of Defense. In addition, his involvement with AAIC has helped him make and strengthen many important contacts in the Alzheimer’s research community — contacts that have advanced his own laboratory.

Today, Dr. Abisambra’s students are enjoying some of the opportunities that were afforded to him by the Association. Shelby Meier, a graduate student in his lab, won an AAIC Travel Fellowship and the Best Poster Award at AAIC in 2015. These honors “gave Shelby exposure to the field to learn, interact, and build collaborations of her own.” In short, Alzheimer’s Association support has not only been vital to Dr. Abisambra’s own career, but it has also helped him foster the careers of a younger generation — just as his early love for research was fostered by his grandfathers.

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