Roles of TREM2 and Protein Prenylation Pathways in Brain Aging and in Alzheimer’s Disease.
Postdoctoral Fellow, Columbia University
Undergraduate and Graduate Institutions and Major:
China Agricultural University, B.S. in Biological Science, 2015
University of Minnesota, MS, Biological Sciences, 2017
Ling Li, DVM, Ph.D., Department of Experimental and Clinical Pharmacology
Description of PhD Research:
Alzheimer’s disease (AD) is a late-onset fatal neurodegenerative disease that affects millions of people without effective treatment. AD is the most common cause of dementia in the elderly which is characterized by progressive loss of cognitive functions. The mechanisms of the disorder remain obscure but emerging evidence has suggested that a post-translational lipid modification of proteins, called prenylation, plays an important role in the pathogenesis of AD. Protein prenylation adds lipid molecules, isoprenoids, to proteins with a characteristic C-terminal motif (CAAX) and facilitates protein-protein and protein-membrane interactions. This reaction is catalyzed by either farnesyltransferase (FT) or geranylgeranyltransferase (GGT). Small GTPases, including the Ras superfamily, are a major target of protein prenylation, and they govern diverse signaling cascades. In AD, modulation of protein prenylation in vitro affects pathological hallmarks of AD including amyloid-β and tau levels. Using a direct genetic approach, recent studies from our lab showed that two protein prenylation pathways play distinct neurophysiological roles. Our previous study and preliminary data have shown that reducing FT systemically or knockout in neurons rescued cognitive functions, mitigated amyloid-β deposition and neuroinflammation in a mouse model of AD. In contrast, reducing GGT systemically or knockout in neurons led to impaired cognitive functions and synaptic plasticity. The cellular and molecular mechanisms of FT shaping synaptic plasticity and AD pathogenesis remain to be further explored. Therefore, the long-term goal of this study is to uncover the cellular and molecular mechanisms of FT and activation of downstream signaling pathways in the early pathogenesis of AD. Because damping FT in AD mice rescued cognitive function and neuropathology, we hypothesize that neuronal FT specific deletion improves synaptic dysfunction in a mouse model of AD. Utilizing the Cre-loxP system to knockout FT in neurons, I will conduct ex vivo field electrophysiology experiments to assess their synaptic plasticity. Since reducing FT in AD mice also alleviated neuroinflammation and microglia had been shown to be the pivotal mediator of neuroinflammation in AD, we hypothesize that FT contributes to microglial proinflammatory responses in AD. To test this hypothesis, I will utilize the Cre-loxP system to knockout FT specifically in microglia and conduct behavioral tests, biochemistry, and immunostaining experiments. The next step is to study the downstream signaling of FT. One potential target is the small GTPase, Hras. Hras is exclusively prenylated by FT and its downstream signaling cascade is activated in AD mice. Therefore, we hypothesize that Hras knockout ameliorates pathology in AD. By crossing Hras knockout mice with AD mice, I will assess AD-related cellular changes in cultured primary neurons, and behavioral, synaptic plasticity, and pathological changes in vivo. Taken together, the results of these experiments will expand our understanding of the cellular and molecular mechanisms of AD pathogenesis, as well as identifying novel therapeutic targets for treating AD.
Graduate Level Publications:
- Mol Neurobiol. 2022 Oct 26. doi: 10.1007/s12035-022-03082-0. Deletion of small GTPase H-ras rescues memory deficits and reduces amyloid plaque-associated dendritic spine loss in transgenic Alzheimer's mice.
- Qu W, Li L. Microglial TREM2 at the intersection of brain aging and Alzheimer's disease. Neuroscientist. 2021 Sep 2:10738584211040786.
- Qu W, Li L. Loss of TREM2 confers resilience to synaptic and cognitive impairment in aged mice. J Neurosci. 2020 Dec 9;40(50):9552-9563.
- Qu W, Suazo KF, Liu W, Cheng S, Jeong A, Hottman D, Yuan LL, Distefano MD, Li L. Neuronal protein farnesylation regulates hippocampal synaptic plasticity and cognitive function. Mol Neurobiol. 2021 Mar;58(3):1128-1144.
- Chernick D, Ortiz-Valle S, Jeong A, Qu W, Li L. Peripheral versus central nervous system ApoE in Alzheimer's Disease: Interplay across the blood-brain barrier. Neurosci Lett. 2019 Aug 24;708:134306.
- Ferro A*, Qu W*, Lukowicz A, Svedberg D, Johnson A, Cvetanovic M. Inhibition of NF-κB signaling in IKKβF/F;LysM Cre mice causes motor deficits but does not alter pathogenesis of Spinocerebellar ataxia type 1. PLoS One. 2018;13(7):e0200013. (*Co-first author)
- Kim JH, Lukowicz A, Qu W, Cvetanovic M. Astroglia contribute to the pathogenesis of spinocerebellar ataxia Type 1 (SCA1) in a biphasic, stage-of-disease specific manner. Glia. 2018;66(9):1972-1987
- Qu W, Johnson A, Kim JH, Lukowicz A, Svedberg D, Cvetanovic M. Inhibition of colony-stimulating factor 1 receptor early in disease ameliorates motor deficits in SCA1 mice. J Neuroinflammation. 2017;14(1):107.
Graduate Oral Presentations:
- Qu W. Turning off a molecular switch to stop Alzheimer’s disease, 3MT competition, Biomedical research day, May 2019, University of Minnesota
- Qu W, Gram A, Li L. Role of triggering receptor expressed in myeloid cells 2 (TREM2) in aging. Poster Presentation, Society for Neuroscience (SfN) 2019.
- Qu W, Hottman D, Liu W, Yuan L, Li L. Two protein prenylation pathways differentially affect synaptic plasticity and cognitive function. Poster presentation, Society for Neuroscience. 2018, San Diego, CA.
- Qu W, Johnson A, Kim JH, Lukowicz A, Svedberg D, Cvetanovic M: Role of microglia in SCA1 – Microglia depletion ameliorates motor behavior deficits in SCA1 mice. Abstract for poster presentation, Translational Neuroscience Institution annual retreat 2017, Wallin Neuroscience Discovery Day 2017, University of Minnesota, Minneapolis, MN.
- Second place in 3-minute thesis competition (3MT), Biomedical sciences graduate programs, University of Minnesota, May 2019
- Minnesota State Fair Brain Booth, 2018
- Neurodegenerative Diseases and Neural Injury
- Synaptic Plasticity and Learning
- Society for Neuroscience
- Michael Lee, Ph.D., Department of Neuroscience
- Wensheng Lin, Ph.D., Department of Neuroscience
- Ling Li, DVM, Ph.D., Department of Experimental and Clinical Pharmacology
Thesis Committee Members:
Marija Cvetanovic, Ph.D., Department of Neuroscience (Chair)
Ling Li, DVM, Ph.D., Department of Experimental and Clinical Pharmacology
Alfonso Araque, Ph.D., Department of Neuroscience
Sylvain Lesne, Ph.D., Department of Neuroscience
Mark Distefano, Ph.D., Deparment of Chemistry
Outstanding Graduates of China Agricultural University, 07/2015
Third-Place Scholarship at China Agricultural University, 10/2014
Second-Place Scholarship at China Agricultural University, 10/2012 and 2013
Merit Students Award at China Agricultural University, 10/2012
Dahuanong Scholarship at China Agricultural University, 10/2012
Undergraduate or Post-Bac Research:
What Got You Interested In Research?
I found my love for research from early experiences. I could never forget the excitement when I first saw cells under a microscope. I was so attracted to the beauty of the complex yet organized biological world that I bought a microscope and built a small laboratory at home when I was in high school. The excitement of learning new things drove me to spend hours and hours exploring ideas. My undergraduate research experience made me realize that I wanted to understand the underlying mechanisms of animal behavior. Therefore, I chose the Masters in Biological Sciences program at the University of Minnesota to focus on neuroscience. As I learned more, I found that studying neurodegenerative diseases not only could reveal more functions of the brain, but also could help patients in real life. Even though the research theme I am interested in has shifted, the happiness of learning and exploring and the excitement of discovery has never changed.
Why Did You Choose MN?
I came to UMN for my Master’s degree, and as I got to know the Graduate Program in Neuroscience, I knew this was the program that could help me to reach my highest potential. First, the four-week course at Itasca not only provides basic neuroscience lab technique training but also offers a great bonding opportunity with classmates and faculty members. Coming back from Itasca, there are four core courses that provide fundamental neuroscience knowledge and will train me to think as a neuroscientist. There are also four lab rotations in the first year that will allow me to find a lab. In addition, there are more than a hundred faculty members with numerous great research projects that cover all kinds of areas in neuroscience. Even though I cannot work with every faculty member, the unique collaborative research environment at the U will help me build networks and provide all the resources I need for my research. These outstanding advantages make the GPN program unique, and I believe this is the program that can train me to become a better scientist.
Student Mentor and the Best Advice They Gave You?
Mariah Wu gave me a lot of precious advice, one of which is to choose a PI that I am more comfortable working with over a project in which I am interested.
Favorite Itasca Memory:
My favorite memory from Itasca is biking around the Lake Itasca. I never thought I could finish a 17-mile bike ride but I did, so I should stop telling myself things I cannot achieve.