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Targeting Tau Aggregation for the Diagnosis and Treatment of Alzheimer’s Disease

Schafer, Nicole D.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1366219959

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Biophysics.
The aggregation of tau protein in the brain is a defining pathological characteristic of several diseases, known as tauopathies, the most common of which is Alzheimer’s disease. Because the temporal and spatial progression of tau lesions correlates with neurodegeneration and cognitive decline, they are an attractive target for diagnostic and therapeutic strategies. Whole-brain imaging is a promising strategy for pre-mortem detection of tau lesions, but the approach is complicated by the high concentrations of potentially confounding binding sites presented by beta-amyloid plaques. Inhibition of tau aggregation using small molecules is a promising strategy for the treatment of tauopathies, but the field lacks an understanding of the inhibitory mechanism of these molecules. Towards the diagnosis of Alzheimer’s disease, a nonlinear, four-tissue-compartmental pharmacokinetic model of diffusion-mediated radiotracer uptake and distribution was developed. This model was used to predict the contributions of relative binding affinity and binding site density to the imaging dynamics and selectivity of a hypothetical tau-directed radiotracer. Initial estimates of nonspecific binding and brain uptake parameters were made by fitting data from a previously published kinetic study of Pittsburgh Compound B, an established amyloid-directed radiotracer. The resulting estimates were then used to guide simulations of tau binding selectivity while assuming early-stage accumulation of disease pathology. The simulations suggest that for tau aggregates to represent at least 80% of specific binding signal, binding affinity or binding site density selectivities for tau over beta-amyloid should be at least 20- or 50- fold, respectively. The simulations also suggest, however, that overcoming nonspecific binding will be an additional challenge for tau-directed imaging agents owing to low concentrations of available binding sites. Overall, nonlinear modeling can provide insight into the performance characteristics needed for tau-directed radiotracers in vivo. Towards the development of Alzheimer’s disease therapeutics, several compounds capable of inhibiting tau aggregation have been identified, including macrocyclic bis-carbocyanines. To extend the structure activity relationship of this inhibitor class, N,N’-alkylene bis-thiacarbocyanines linked by three to nine carbon alkyl chains were synthesized and examined for inhibitory activity in vitro. Inhibitory potency followed a biphasic pattern with a clear optimum linker length of 4 – 7 methylene units. On the basis of absorbance spectroscopy measurements, inhibitory potency correlated with the concentration of open monomer conformation rather than with the concentration of bulk compound. These data suggest that inhibitory potency can be optimized at the level of open monomer conformation through control of linker length. Other compound scaffolds that support potent inhibitors of tau aggregation include non-cyclic carbocyanines, phenothiazines, triarylmethines, and rhodanines. A study of these compound families reveals polarizability as the key molecular characteristic for generating inhibitory potency. Further analysis with the most potent non-cyclic cyanine revealed the stabilization of a soluble, off-pathway tau oligomer. These results further our understanding of the mechanism of tau aggregation inhibition towards the treatment of Alzehimer’s disease.
Jeff Kuret, Ph.D. (Advisor)
Gunjan Agarwal, Ph.D. (Committee Member)
Richard Swenson, Ph.D. (Committee Member)
Michael Tweedle, Ph.D. (Committee Member)
115 p.
Biophysics
Alzheimer's disease; tau protein aggregation; small molecule binding and inhibition

Recommended Citations

Citations

  • Schafer, N. D. (2013). Targeting Tau Aggregation for the Diagnosis and Treatment of Alzheimer’s Disease [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366219959

    APA Style (7th edition)

  • Schafer, Nicole. Targeting Tau Aggregation for the Diagnosis and Treatment of Alzheimer’s Disease. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1366219959.

    MLA Style (8th edition)

  • Schafer, Nicole. "Targeting Tau Aggregation for the Diagnosis and Treatment of Alzheimer’s Disease." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366219959

    Chicago Manual of Style (17th edition)

osu1366219959
524
© 2013, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.