Inhibition of tau polymerization with a cyanine dye in two distinct model systems.
In a host of neurodegenerative diseases Tau, a microtubule-associated protein, aggregates into insoluble lesions within neurons. Previous studies have utilized cyanine dyes as Tau aggregation inhibitors in vitro. Herein we utilize cyanine dye 3,3'-diethyl-9-methyl-thiacarbocyanine iodide (C11) to modulate Tau polymerization in two model systems, an organotypic slice culture model derived from Tau transgenic mice and a split green fluorescent protein complementation assay in Tau-expressing cells. In slice cultures, submicromolar concentrations (0.001 microm) of C11 produced a significant reduction of aggregated Tau and a corresponding increase in unpolymerized Tau. In contrast, treatment with a 1 microm dose promoted aggregation of Tau. These results were recapitulated in the complementation assay where administration of 1 microm C11 produced a significant increase in polymerized Tau relative to control, whereas treatment of cells with 0.01 microm C11 resulted in a marked reduction of aggregated Tau. In the organotypic slice cultures, modulation of Tau aggregation was independent of changes in phosphorylation at disease and microtubule binding relevant epitopes for both dosing regimes. Furthermore, treatment with 0.001 microm C11 resulted in a decrease in both total filament mass and number. There was no evidence of apoptosis or loss of synaptic integrity at either dose, however, whereas submicromolar concentrations of C11 did not interfere with microtubule binding, higher doses resulted in a decrease in the levels of microtubule-bound Tau. Overall, a cyanine dye can dissociate aggregated Tau in an ex vivo model of tauopathy with little toxicity and exploration of the use of these type of dyes as therapeutic agents is warranted.
Congdon
Erin E
EE
Department of Pathology, Taub Institute, Columbia University and Department of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York 10032, USA.
Figueroa
Yvette H
YH
Wang
Lili
L
Toneva
Galina
G
Chang
Edward
E
Kuret
Jeff
J
Conrad
Christopher
C
Duff
Karen E
KE
D000818:Animals; D001681:Biological Assay / Q000379:methods*; D001704:Biopolymers / Q000378:metabolism*; D002232:Carbocyanines / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000648:ultrastructure; D010766:Phosphorylation; D046509:Tissue Culture Techniques / Q000379:methods*; D014022:Tissue Survival; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism*
C484503:3,3'-diethyl-9-methylthiacarbocyanine iodide; D001704:Biopolymers; D002232:Carbocyanines; D016875:tau Proteins; D049452:Green Fluorescent Proteins