Role of eEF2 Hyper-phosphorylation in Alzheimer’s-associated Synaptic Failure and Memory Deficits
The basic causes underlying the cognitive deterioration in Alzheimer’s disease (AD) and other dementias remain elusive, which hampers the development of any effective therapies. This project will shed light on whether new proteins synthesized in association with a cellular signaling factor (eEF2K/eEF2 signaling) play a role in AD pathogenesis This work could inform future identification of novel diagnostic markers and therapeutic targets for AD and related cognitive syndromes.
The goal of our project is to understand the detailed mechanisms underlying AD, and particularly the role of a messenger RNA (mRNA) known as translational factor elongation factor 2 (eEF2) in AD-associated dementia syndrome. There are three aims for this project. For Aim 1, we seek to determine whether restoration of normal eEF2 activity rescues AD-associated impairments in synaptic plasticity, in a cellular model of learning and memory. In Aim 2, we will investigate whether normalization of eEF2 activity improves learning and memory defects in a mouse model of AD. In Aim 3, we plan to study whether AD-associated impairments of protein synthesis (mRNA translation) are alleviated by normalizing eEF2 activity. Lack of understanding of the molecular mechanisms underlying AD hinders the development of novel therapeutic targets and diagnostic biomarkers for the disease. Our work takes advantage of multiple state-of-the-art techniques and approaches, which enables us to identify, for the first time, detailed molecular mechanisms underlying protein synthesis defects associated with eEF2 signaling dysregulation in AD. Moreover, we use two sets of novel methods to measure de novo protein synthesis, which should provide important insights into the disease etiology. Completion of the project can contribute important data with regards to the signaling mechanisms underlying AD’s onset and progression. Future studies will build on the results from this project and our other research findings on AD-related protein synthesis dysregulation to inform the eventual development of novel diagnostic markers and better therapeutic strategies for AD-related cognitive syndromes, for which no effective treatments exist.
About the Researcher
Dr. Tao Ma received his MD in China and his PhD in neuroscience from Mount Sinai School of Medicine at New York in 2008, working with Drs. Robert Blitzer and Emmanuel Landau. From 2008-10, he was a postdoctoral research fellow with Dr. Gunnar Gouras in the Department of Neurology and Neuroscience at Weill Cornell Medical College of Cornell University, New York City. From 2010-14, he was an assistant research scientist, and then research assistant professor at the New York University Center for Neural Science, in the laboratory of Dr. Eric Klann. Since 2014, Dr. Ma has been a tenure-track assistant professor at Wake Forest University School of Medicine in Winston-Salem, NC, within the Department of Internal Medicine, Gerontology and Geriatric Medicine. Dr. Ma is a neuroscientist with a specialization in learning, memory, and synaptic plasticity. His research focuses on novel molecular mechanisms underlying pathophysiology of Alzheimer’s disease (AD) and seeks to identify potential therapeutic targets or biomarkers for AD and other aging-related cognitive impairments. Primary techniques applied in his laboratory include electrophysiology, confocal microscopy, behavioral tests, and molecular approaches in transgenic mouse models. His original research findings on molecular mechanisms in AD have been published in many high-profile peer-reviewed journals, including The Journal of Neuroscience and Nature Neuroscience, garnering international attention. Dr. Ma has won numerous awards. He is a recipient and principal investigator of National Institute of Health/National Institute of Aging K99/R00 and R01 research grants, and the Alzheimer’s Association New Investigator award. He has been an editor of the International Journal of Neurology Research,” and associate editor of the Journal of Alzheimer’s Disease. He is a member of the Society for Neuroscience and the New York Academy of Science.
I got my PhD in Neuroscience from Mount Sinai School of Medicine in New York City. My PhD work focused on studying signaling mechanisms underlying synaptic plasticity, a cellular model for learning and memory. When I started looking for a postdoc position, I decided that I want to make my PhD work “translational”, and work on a disease to which I can apply what I learned from the graduate school. Alzheimer’s disease (AD) was just such a natural choice for me. Working on AD changes my whole science career path. Looking back, I believe this is one of the best decisions I have ever made in my life. AD has reached an epidemic status in the United States and across the world, yet there is basically nothing we can do about the disease. There is so much more we need to know about the mechanisms underlying AD to help develop novel therapeutics.
I was fortunate to get my first BrightFocus grant when I was a postdoctoral fellow at the New York University. I was then in a critical phase of transitioning from the role of a postdoctoral trainee to becoming an independent principal investigator, i.e., starting my own laboratory. The award has been of tremendous help to me in establishing my own research projects and achieving my scientific career goals of finding a cure/therapy for AD and other aging-related cognitive syndromes. As a matter of fact, I got multiple offers and accepted a highly competitive tenure-track faculty position at Wake Forest University School of Medicine. The grant that I am awarded from the BrightFocus Foundation certainly helped in that success. Now that I am at another critical point of my scientific career, and working to expand our research activities on AD, the arrival of this BrightFocus grant is just in time. With that, I am truly grateful to the Foundation and all the generous donors.
Yang W, Zhou X, Zimmermann HR, Ma T. Brain-specific suppression of AMPKα2 isoform impairs cognition and hippocampal LTP by PERK-mediated eIF2α phosphorylation. Molecular Psychiatry. 2020 May 4:1-8. PUBMED: 32366952 Yang W, Zhou X, Zimmermann HR, Ma T. Brain-specific suppression of AMPKα2 isoform impairs cognition and hippocampal LTP by PERK-mediated eIF2α phosphorylation. Molecular Psychiatry. 2020 May 4:1-8. PUBMED: 32366952
Day, S. M., Yang, W., Wang, X., Stern, J. E., Zhou, X., Macauley, S. L., & Ma, T. (2019). Glucagon-like peptide-1 cleavage product improves cognitive function in a mouse model of Down syndrome. eNeuro, ENEURO-0031. PMID: 31040160 DOI: 10.1523/ENEURO.0031-19.2019
First published on: July 26, 2017
Last modified on: May 12, 2020