Distinct Tau Strains: Exploring Variability in Cell Uptake and Seeding Using Heparinoids




Prueitt, William

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BACKGROUND: Tauopathies (including Alzheimer's Disease) are incurable, progressive neurodegenerative diseases caused by tau protein aggregation. Evidence suggests that tau aggregates spread pathology as do prions, infectious proteins that transmit a pathologic conformation to native proteins via disease-specific conformers (strains). Evidence shows tau aggregates enter cells through heparan sulfate proteoglycan (HSPG) mediated macropinocytosis. In this project, I explored whether distinct tau strains bind cell surface HSPGs uniquely or generically to trigger uptake and used heparinoids to measure the relative importance of heparin size and sulfation patterns. METHODS: I used a "biosensor" cell line responsive to tau aggregates that scores induction of intracellular aggregation based on FRET flow cytometry. Using cell lysate from various strains of tau, I measured (1) the ability of different heparin-like molecules to block tau aggregate uptake and seeding, and (2) seeding in HSPG gene knockout cells. RESULTS: All tau strains tested were highly sensitive to heparin inhibition of seeding and most maintained a highly similar dose response. Some strains, however, showed subtle differences. At maximal heparin concentrations, noticeably higher seeding vs baseline was observed in DS 5 & 6 (17%, 9%) as compared to the other strains (<5%). Heparinoid titrations revealed highly similar inhibition patterns between DS 9 and 10. Seeding reduction: DS 9: dp4= 21%; dp8= 27%; dp12= 70%; dp16= 63%; De-2-O=65%; De-6-O= 52%; De-N= 35%. For DS 10: dp4= 19%; dp8= 33%; dp12= 64%; dp16=46%; De-2-O= 53%; De-6-O= 25%; De-N= 13%. Seeding in HSPG genetic knockout cells was reduced substantially in two knockouts, but increased in another. CONCLUSIONS: Cellular uptake of many tau strains is similarly inhibited by heparin, hinting that the same heparinoid (or small molecule analog) could be used to treat diverse tauopathies. But the unique behavior of some strains suggests a one-size-fits-all treatment approach may not always be sufficient. Certain size and sulfation patterns on heparin have specific importance for tau binding. Larger heparinoids better inhibit tau seeding (dp16 & dp12 > dp8 & dp4) and the importance of N-sulfation > 6-O-sulfation > 2-O-sulfation. This pattern remains consistent in recombinant tau, DS 9, DS 10, and in the genetic knockout data gathered here (using strains) and by others in the lab (using recombinant tau). This data shows many similarities and some differences between strains of tau. Parsing these differences could have important implications for understanding the diversity of tauopathies and finding unique approaches to diagnosis and treatment.

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The 56th Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 23, 2018, 2-5 p.m., D1.600)

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Prueitt, W., Stopschinski, B., & Diamond, M. (2018, January 23). Distinct tau strains: exploring variability in cell update and seeding using heparinoids. Poster session presented at the 56th Annual Medical Student Research Forum, Dallas, TX. Retrieved from https://hdl.handle.net/2152.5/5324

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