Synapses are specialized structures that are critical for the transmission of information between neurons in the brain. Fine-tuning of the electrochemical activity at synapses underlies cognitive processes. In Alzheimer’s disease, memory loss coincides with synapse deterioration. The Tracy lab is investigating the molecular events that lead to synapse dysfunction and cognitive decline in Alzheimer’s disease and frontotemporal dementia. We think that synapses are particularly vulnerable to toxicity early in the progression of dementia before neurons begin to die. Tau, a microtubule-associated protein, accumulates in the brain and becomes toxic to neurons in Alzheimer’s disease and frontotemporal dementia. We are exploring how tau-mediated toxicity contributes to the emergence of synapse pathophysiology in these diseases. We are using mouse models and human induced pluripotent stem cell (iPSC)–derived neurons to dissect the mechanisms that trigger synapse and neuronal dysfunction during pathogenesis. Our long-term goal is to establish a foundation for new treatment strategies to restore synapse function and cognition at the early stages of disease progression before neurons are lost.
Why it matters
Millions of people are suffering from progressively debilitating dementia as they age, and the number of people diagnosed with Alzheimer’s disease is steadily rising. To advance our understanding of the mechanisms that promote cognitive decline in Alzheimer’s disease and frontotemporal dementia, it will be critical to discover the events that lead to synapse dysfunction and deterioration. This research may uncover new approaches for therapeutic intervention early in disease progression to promote the healthy aging of the brain.
It’s becoming obvious that intervening early in the disease process is essential in order to promote healthy aging of the brain. My lab is focused on discovering the early events that lead to neurodegeneration.
Tara Tracy, PhD
Dr. Tracy received her PhD in neuroscience from the University of California, Berkeley. She obtained postdoctoral training at the Gladstone Institute of Neurological Disease and University of California, San Francisco. Dr. Tracy was awarded a Ruth L. Kirschstein National Research Service Award from the National Institute on Aging and a BrightFocus Foundation Fellowship for her postdoctoral research to uncover mechanisms that promote memory loss in Alzheimer’s disease. She has received awards in recognition of her work from the Alzheimer’s Association and the Society for Neuroscience. Dr. Tracy’s research is currently supported by a Research Career Development Award from the National Institute on Aging.
J. C.Jackson Chen Research Associate
Kirsten Chui PhD Candidate, USC-Buck Biology of Aging Program
Kirsten earned her B.S. in chemical biology from the University of California, Berkeley. Prior to joining the University of Southern California-Buck Biology of Aging PhD program, she worked on ameliorating age-related cognitive decline and understanding muscle stem cells and muscle regeneration under the mentorship of Dr. Saul Villeda and Dr. Andrew Brack respectively at the University of California, San Francisco. In the Tracy lab, she will be studying the mechanism of loss of memory in tauopathies with the goal of identifying therapeutic strategies.
Grant Kauwe, PhD Staff Scientist
Dr. Kauwe received his undergraduate degree in biology at the University of Hawaii at Manoa and his PhD in neuroscience at the University of California, Berkeley. He received postdoctoral training at the Buck Institute, where he focused on how diet regulates neuronal function. In the Tracy lab, he is investigating the dysregulation of plasticity at synapses underlying memory loss in neurodegenerative disease.
Doyle Lokitiyakul PhD Candidate, USC-Buck Biology of Aging Program
Doyle received his undergraduate BA degree in biology from Washington University in St. Louis. Currently, he is a graduate student from the University of Southern California-Buck Biology of Aging Ph.D. program, joining the Lei lab in July 2020. As an undergrad, his main focus was on NAD+ and its regulatory effects on the aging process. During his undergraduate project, he participated in a CRISPR Cas9 screen, aiming to determine which protein was responsible for a sudden decrease in NAD levels within macrophages during inflammation: a phenomenon that is hypothesized to contribute to age related inflammation. Currently, as a member of the Lei lab, he is interested in studying how oocytes maintain their molecular integrity and functions with age. During his free time Doyle enjoys reading long science fiction/epic fantasy novels and practicing Muay Thai.
Kristeen Pareja, PhD Postdoctoral Research Fellow
Dr. Pareja-Navarro is originally from Los Baños Laguna, Philippines. She earned her BS Degree in Biochemistry and Molecular Biology from UC Davis and her PhD in Pharmacology from Cornell University. Prior to attending graduate school, she worked in several labs including Lawrence Berkeley National Laboratory, Novozymes and Touro University. As a graduate student in the Sevier lab, she studied chaperone proteins involved in oxidative stress signaling. She joined the Tracy lab in December 2019 where she is currently investigating the role of tau oligomers in synapse dysfunction.
- Tracy, T. E., Gan, L. (2018). Tau-mediated synaptic and neuronal dysfunction in neurodegenerative disease. Current Opinion of Neurobiology, 51, 134–138.
- Martinez-Losa, M. M.*, Tracy, T. E.*, Ma, K.*, Khan, A., Verret, L., Clemente, A., Cobos, I., Ho, K., Gan, L., Mucke, L., Alvarez-Dolado, M., Palop, J. J. (2018). Nav1.1-overexpressing interneuron transplants restore brain rhythms and cognition in a mouse model of Alzheimer’s disease. Neuron, 98, 75–89.
- Wang, C., Ward, M., Chen, R., Liu, K., Tracy, T. E., Chen, X., Xie, M., Sohn, P. D., Ludwig, C., Meyer-Franke, A., Ding, S., Gan, L. (2017). Scalable production of iPSC-derived human neurons to identify novel tau-lowering compounds by high-content screening. Stem Cell Reports, 9, 1221–1233.
- Tracy, T. E., Gan, L. (2017). Acetylated tau in Alzheimer’s disease: An instigator of the synaptic dysfunction underlying memory loss. BioEssays, 39, 4.
- Sohn, P. D.*, Tracy, T. E.*, Son, H. I., Zhou, Y., Leite, R., Miller, B., Seeley, W. W., Grinberg, L., Gan, L. (2016). Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment. Molecular Neurodegeneration, 11, 47.
- Tracy, T. E., Sohn, P. D., Minami, S. S., Wang, C., Min, S. W., Zhou, Y., Li, Y., Le, D., Lo, I., Ponnusamy, R., Cong, X., Schilling, B., Ellerby, L., Huganir, R. L., Gan, L. (2016). Acetylated tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron, 90, 245–60.