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Journal Article

Suppressing Tau Aggregation and Toxicity by an Anti-Aggregant Tau Fragment.

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Mandelkow, Eckhard
Neuronal Cytoskeleton and Alzheimer's Disease, Cooperations, Center of Advanced European Studies and Research (caesar), Max Planck Society;

Mandelkow, Eva-Maria
Neuronal Cytoskeleton and Alzheimer's Disease, Cooperations, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Citation

Pir, G. J., Choudhary, B., Kaniyappan, S., Chandupatla, R. R., Mandelkow, E., Mandelkow, E.-M., et al. (2019). Suppressing Tau Aggregation and Toxicity by an Anti-Aggregant Tau Fragment. Molecular Neurobiology, 56(5), 3751-3767. doi:10.1007/s12035-018-1326-z.

Abstract

Tau aggregation is a hallmark of a group of neurodegenerative diseases termed Tauopathies. Reduction of aggregation-prone Tau has emerged as a promising therapeutic approach. Here, we show that an anti-aggregant Tau fragment (F3ΔKPP, residues 258-360) harboring the ΔK280 mutation and two proline substitutions (I277P & I308P) in the repeat domain can inhibit aggregation of Tau constructs in vitro, in cultured cells and in vivo in a Caenorhabditis elegans model of Tau aggregation. The Tau fragment reduced Tau-dependent cytotoxicity in a N2a cell model, suppressed the Tau-mediated neuronal dysfunction and ameliorated the defective locomotion in C. elegans. In vitro the fragment competes with full-length Tau for polyanionic aggregation inducers and thus inhibits Tau aggregation. Our combined in vitro and in vivo results suggest that the anti-aggregant Tau fragment may potentially be used to address the consequences of Tau aggregation in Tauopathies.