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Small-Molecule Mediated Neuroprotection in an In Situ Model of Tauopathy

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Abstract

Small-molecule inhibitors of neurofibrillary lesion formation may have utility for treatment of Alzheimer’s disease and certain forms of frontotemporal lobar degeneration. These lesions are composed largely of tau protein, which aggregates to form intracellular fibrils in affected neurons. Previously it was shown that chronic overexpression of human tau protein within identified neurons (anterior bulbar cells) of the sea lamprey induced a phenotype-resembling tauopathic neurodegeneration, including the formation of tau filaments, fragmentation of dendritic arbors, and eventual cell death. Development of this neurodegenerative phenotype was blocked by chronic administration of a benzothiazole derivative termed N3 ((E)-2-[[4-(dimethylamino)phenyl]azo]-6-methoxybenzothiazole) to lamprey aquaria. Here we examined the mechanism of action of N3 and an alkene analog termed N4 ((E)-2-[2-[4-(dimethylamino)phenyl]ethenyl]-6-methoxybenzothiazole) in vitro and in the lamprey model. Results showed that although both compounds entered the lamprey central nervous system, only N3 arrested tauopathy. On the basis of in vitro aggregation assays, neither compound was capable of directly inhibiting tau filament formation. However, N3, but not N4, was capable of partially antagonizing the binding of Thioflavin S to synthetic tau filaments. The results suggest that occupancy of N3-binding sites on nascent tau filaments may significantly retard the progressive degeneration accompanying tau overexpression in lamprey.

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Acknowledgments

We thank Xian Yu for assistance with ThS fluorescence assays, Carmen Chirita and Mihaela Necula for electron microscopy images, and Jun Yao for immunohistochemical processing of lamprey samples. This research was supported by grants from the National Institutes of Health (AG14452 and MH077621; J.K.; AG018661; A.A.), and the Alzheimer’s Association (IIRG-05-14288; J.K.).

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Authors and Affiliations

  1. Department of Molecular & Cellular Biochemistry, Center for Molecular Neurobiology, College of Medicine, The Ohio State University, 1060 Carmack Rd., Columbus, OH, 43210, USA

    Nicolette S. Honson, Jordan R. Jensen & Jeff Kuret

  2. Department of Chemistry and Physics, Chicago State University, Chicago, IL, 60628, USA

    Aida Abraha

  3. Department of Biological Sciences, University of Massachusetts, Lowell, MA, 01854, USA

    Garth F. Hall

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  1. Nicolette S. Honson
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  2. Jordan R. Jensen
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  5. Jeff Kuret
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Correspondence to Jeff Kuret.

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Honson, N.S., Jensen, J.R., Abraha, A. et al. Small-Molecule Mediated Neuroprotection in an In Situ Model of Tauopathy. Neurotox Res 15, 274–283 (2009). https://doi.org/10.1007/s12640-009-9028-y

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  • DOI: https://doi.org/10.1007/s12640-009-9028-y

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