Targeting Distinct Tau Strains and Tau Aggregate Sizes with Heparin and Heparinoids to Explore Differential Inhibition of Cell Uptake and Seeding

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dc.contributor.otherStopschinski, Barbaraen
dc.contributor.otherDiamond, Marcen
dc.creatorPrueitt, Williamen
dc.date.accessioned2017-02-10T18:32:02Z
dc.date.available2017-02-10T18:32:02Z
dc.date.issued2017-01-17
dc.descriptionThe 55th Annual Medical Student Research Forum at UT Southwestern Medical Center (Monday, January 17, 2017, 2-5 p.m., D1.600)en
dc.descriptionEach year the Medical Student Research Program awards students for the best oral presentation and the best poster presentation as judged by faculty across campus. This author received an award as one of the best poster presentations at this forum.en
dc.description.abstractBACKGROUND: 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 strains--disease-specific conformers that propagate indefinitely in living systems. Like prion protein, tau also forms strains. It is unknown whether each binds the cell surface heparan sulfate proteoglycans in a unique or generic fashion to trigger uptake. METHODS: I used a "biosensor" cell line responsive to tau aggregates that scores induction of intracellular aggregation based on FRET flow cytometry. I tested the ability of different heparin-like molecules to block tau aggregate uptake and seeding. I measured tau uptake and induction of intracellular aggregation of a reporter. RESULTS: Tau seeding was comparably inhibited by heparin regardless of aggregate size. Data from testing two strains (Clone 9 & 10) for heparin inhibition of cell seeding suggested that they have differential sensitivity (DS9: IC50 = 335.9nM & DS10: IC50 = 2.1uM). Testing 9 heparinoids for tau seeding inhibition indicated that they had highly variable inhibition, some having no effect and some having an effect nearly as strong as heparin. CONCLUSIONS: This data suggests that (1) tau seeding is similarly inhibited by heparin regardless of tau aggregate size, and that (2) seeding of different strains of tau may be variably inhibited by heparin, hinting that specificity and avidity may differ by strain. If true, this knowledge will be applicable across many tauopathies and may influence diagnosis (because tau strains can differentiate pathology) and treatment (strain-specific therapies may be required). This data also indicated that certain size and sulfation patterns of heparin affect seeding inhibition. This matches other data produced in the lab using genetic knockouts, and supports the idea that crucial binding domains on heparin are necessary for pathologic tau spread between cells.en
dc.description.sponsorshipSouthwestern Medical Foundationen
dc.identifier.citationPrueitt, W., Stopschinski, B., & Diamond, M. (2017, January 17). Targeting distinct tau strains and tau aggregate sizes with heparin and heparinoids to explore differential inhibition to cell uptake and seeding. Poster session presented at the 55th Annual Medical Student Research Forum, Dallas, TX. Retrieved from https://hdl.handle.net/2152.5/4036en
dc.identifier.urihttps://hdl.handle.net/2152.5/4036
dc.language.isoenen
dc.relation.ispartofseries55th Annual Medical Student Research Forumen
dc.subjectBasic Research and Disease Modelsen
dc.subject.localBest Poster Presentation Awarden
dc.subject.meshCell Culture Techniquesen
dc.subject.meshHeparan Sulfate Proteoglycansen
dc.subject.meshHeparinen
dc.subject.meshHeparinoidsen
dc.subject.meshtau Proteinsen
dc.subject.meshTauopathiesen
dc.titleTargeting Distinct Tau Strains and Tau Aggregate Sizes with Heparin and Heparinoids to Explore Differential Inhibition of Cell Uptake and Seedingen
dc.typePresentationen

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