Tauopathies affect more than 6 million people in the US and include Alzheimer’s disease, progressive supranuclear palsy, and frontotemporal dementia. In a subset of these diseases, genetic changes in MAPT, the gene that encodes the tau protein, initiate a cascade of events that leads to tau aggregation and death of neuronal populations in the brain. Some regions in the central nervous system are routinely affected in tauopathies, while other regions are spared. The cascade of events that leads to disease and that underlies cell-type specific vulnerability remains poorly understood. Due to the complexities of the MAPT gene and its expression patterns, current cell and mouse models have not resolved the mechanisms by which fully penetrant disease mutations or risk variants in MAPT disrupt the tau protein and cause disease in a cell-type specific manner. The primary objective for this pilot grant is to use two cell-fate reprogramming systems to generate human neurons and to test the feasibility of these experimental conditions to study tauopathies. Starting from the same human fibroblasts, we will i) generate neurons differentiated from induced pluripotent stem cells; and ii) use microRNAs and neural transcription factors to directly convert fibroblasts into neurons. By enriching the population of neuronal subtypes from the reprogramming conditions, we hope to understand neuronal subtype-specific vulnerability underlying tauopathies. Together, this study will use novel human cell models that will begin to define the cascade of events that lead to neurodegenerative tauopathies and will provide avenues for advancement in therapeutic intervention.
Grants and Awards
Rainwater Charitable Foundation (Karch PI)
“IPSC Modeling of AD Using Progerin”
NIH R01 AG056293 (Sally Temple PI; Karch, Co-I)
Narrative Age is the strongest risk factor for Alzheimer’s disease (AD). Yet cell and animal models of AD fail to recapitulate human aging and fail to capture key aspects of disease pathology. In this project, we will increase the level of the protein progerin, which induces cellular abnormalities associated with aging, in human induced pluripotent stem cell lines derived from patients with AD versus healthy individuals. These cells will be differentiated into brain cells that are vulnerable in AD, with the goal of defining how abnormalities associated with aging contribute to the onset and progression of AD pathology.
Christine J Huh, Bo Zhang, Matheus B Victor, Sonika Dahiya, Luis FZ Batista, Steve Horvath, Andrew S Yoo. Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts. eLife ;5:e18648, (2016).
Li Z, Del-Aguila JL, Dube U, Budde J, Morris JC, Bateman RJ, DIAN, Dougherty JD, Lee JM, Karch CM, Cruchaga C, Harari O. (2018). Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure. Genome Medicine. Jun 8;10(1):43.
Jiang S, Wen N. Li Z, Dube U, Del Aguila J, Budde J, Martinez R, Hsu S, Fernandez MV, Cairns NJ, DIAN, IFGC, Harari O, Cruchaga C, Karch CM. (2018). Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP. Translational Psychiatry. Dec 13;8(1):265.
Wang C, Ward M, Chen R, Liu K, Tracy T, Chen X, Xie M, Sohn PD, Ludwig C, Meyer-Franke A, Karch CM, 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. Oct 10;9(4):1221-1233.
Updated January 2019
Hope Center Investigators
Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty on this team, click below.