Jaya Padmanabhan, Ph.D.
Assistant Professor of Molecular Medicine, Johnnie B. Byrd, Sr. Alzheimer's Center & Research Institute, University of South Florida, Tampa, recipient of a 2008 Investigator-Initiated Research Grant
I am grateful to the Alzheimer's Association for providing me with the first independent grant of my scientific career, an Investigator-Initiated Research Grant (IIRG), in 2008. I found out about this while we were traveling north, taking our daughter to a music camp in Vermont. My eyes welled with tears when I read the e-mail from the Association. The award came during a very hard time. The Byrd Alzheimer's Institute had just started, and the money situation was tight. This was when I found out that the Alzheimer's Association was going to fund our research. I am really thankful to this great organization for their timely help.
Impact of Association funding
The grant from the Alzheimer's Association provides funding to help our laboratory examine the role of inflammatory proteins (proteins associated with inflammation) in Alzheimer's disease.
The major hallmarks of Alzheimer's disease are protein aggregates known as amyloid plaques and neurofibrillary tangles. Our laboratory is interested in understanding the molecular, cellular and biochemical changes in the brain that lead to plaques and tangles. Two proteins associated with plaques and tangles are beta-amyloid, a fragment of the amyloid precursor protein (APP), and tau. The grant from the Alzheimer's Association provides funding to help our laboratory examine the role of inflammatory proteins (proteins associated with inflammation) in Alzheimer's disease. Among these proteins are apolipoprotein E e4 (ApoE-e4), alpha 1-antichymotrypsin (ACT), cytokines and complement factors. We are currently analyzing the significance of ACT in Alzheimer's disease.
alpha 1-antichymotrypsin (ACT) protein and Alzheimer's
ACT is present in abnormally high numbers in cells called astrocytes that surround plaques in the Alzheimer's brain. Higher levels of ACT have been reported in cerebrospinal fluid from people with Alzheimer's, signifying that elevated levels of ACT could serve as a biomarker for early detection and diagnosis of Alzheimer's. Previous studies have shown that ACT helps individual beta-amyloid proteins stick together to form small clumps called oligomers. These clumps are much smaller than plaques and precede the development of plaques.
The combination of ACT and beta-amyloid seems to be more toxic to brain nerve cells tested in cell culture experiments than beta-amyloid itself, suggesting that this combination may have deleterious effects in brains as well as in brain cells. Other studies in mice that were genetically engineered to produce Alzheimer's and that produced excess ACT and APP showed that excess ACT accelerated the development of Alzheimer's brain and behavioral changes. How ACT brings about these changes is not clearly understood. Beta-amyloid is generated when APP is clipped first by the enzyme beta-secretase and then by the enzyme gamma-secretase. Whether ACT affects these enzymes is currently being examined.
In addition to its effects on beta-amyloid, in cell culture studies of neurons from the cortex region of the brain, we found that ACT induces the protein tau to take on additional phosphate molecules (called phosphorylation). Purified ACT from human plasma was used for these studies. Neurons treated with the purified ACT showed a significant increase in phosphorylation at three particular sites on the tau protein that have been shown to be affected in Alzheimer's disease.
Analysis of enzymes called kinases that are involved in tau phosphorylation showed that ACT increases the activity of the kinases ERK (extracellular signal-regulated protein kinase) and GSK-3 (glycogen synthase kinase 3). This suggests that one or both of these kinases may be involved in the tau phosphorylation that occurs with excess levels of ACT. This also implies that inhibiting the activity of these kinases may help prevent the changes in beta-amyloid and tau that are hallmarks of Alzheimer's. We hope to pinpoint the molecules involved in this process and use the information to develop drugs targeting these molecules, which may prove beneficial in treating the disease.
Examining proteins and cell division
The second project in our laboratory is to determine the significance in Alzheimer's of proteins associated with cell division. These proteins are present in increased numbers in the Alzheimer's brain. Neurons are non-dividing cells. Excess cell division proteins in the brain may disturb the normal function of neurons. Several investigators, we among them, have shown that inhibiting cell division in neurons grown in the lab protects them from degeneration and death. Results from several studies suggest that Alzheimer's is like cancer, except that in cancer, cell division leads to an increase in cancer cells, while in Alzheimer's it leads to the degeneration and death of non-dividing neurons. By studying the differences and similarities between dividing cells and non-dividing neurons, we hope to gain information that will help us identify potential drug targets for Alzheimer's and cancer.
Moving research forward
The IIRG from the Alzheimer's Association has helped advance both my research and my career. The grant helped me obtain a tenure-track faculty position in the Department of Molecular Medicine at the College of Medicine, University of South Florida, Tampa. I hope to do my best to help the scientific community find a cure or a way to prevent Alzheimer's disease. We believe that a thorough knowledge of the molecular mechanisms involved in the development of Alzheimer's will help us generate novel therapies targeted toward neurodegenerative diseases, and funding from the Alzheimer's Association will help immensely in reaching this goal.
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