Progressive accumulation of microtubule-associated protein (tau) is a defining feature of Alzheimer's disease (AD) and a number of other disorders termed tauopathies. Recent studies from our laboratories, confirmed by others, demonstrated that tau oligomers constitute distinctly toxic and pathologically significant tau species able to spread in tauopathy brain, likely through inter-synaptic transmission. However, precise investigation of tau oligomer spreading is hindered by the complexity of the neuronal network. Methods to effectively diagnose AD and other tauopathies at early stages and monitor their progress are also lacking. In addition to cognitive abnormalities, AD patients show visual anomalies. In this application, we will test the hypothesis that tau pathology in the retina may predict tau-related dysfunction in the brain, making it an excellent platform to study the propagation of tau oligomeric strains, detect and monitor the progression of AD and other tau-related disorders, and evaluate the efficacy of our newly developed tau oligomer-specific monoclonal antibodies (TOMAs) at targeting different tau oligomeric strains. Outcomes from this study will provide clear pathways of oligomer spreading and aid in the development of novel approaches to monitor and treat tauopathies.

Public Health Relevance

Millions of people are affected by Alzheimer's (AD) and other neurodegenerative tauopathies, a large group of disorders characterized by the presence of tau protein aggregates in the brain. The useful and diverse results from this research proposal will have great potential to advance non-invasive diagnostic and therapeutic approaches designed to target pathological tau and inflammation in AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Yang, Austin Jyan-Yu
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University of Texas Med Br Galveston
Schools of Medicine
United States
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Sengupta, Urmi; Carretero-Murillo, Mariana; Kayed, Rakez (2018) Preparation and Characterization of Tau Oligomer Strains. Methods Mol Biol 1779:113-146
Castillo-Carranza, Diana L; Guerrero-Muñoz, Marcos J; Sengupta, Urmi et al. (2018) ?-Synuclein Oligomers Induce a Unique Toxic Tau Strain. Biol Psychiatry 84:499-508
Ghag, Gaurav; Bhatt, Nemil; Cantu, Daniel V et al. (2018) Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior. Protein Sci 27:1901-1909
Sengupta, Urmi; Montalbano, Mauro; McAllen, Salome et al. (2018) Formation of Toxic Oligomeric Assemblies of RNA-binding Protein: Musashi in Alzheimer's disease. Acta Neuropathol Commun 6:113
Ha, Yonju; Liu, Wei; Liu, Hua et al. (2018) AAV2-mediated GRP78 Transfer Alleviates Retinal Neuronal Injury by Downregulating ER Stress and Tau Oligomer Formation. Invest Ophthalmol Vis Sci 59:4670-4682
Gerson, Julia E; Farmer, Kathleen M; Henson, Natalie et al. (2018) Tau oligomers mediate ?-synuclein toxicity and can be targeted by immunotherapy. Mol Neurodegener 13:13