2009
DOI: 10.1074/jbc.m109.016089
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Inhibition of Tau Polymerization with a Cyanine Dye in Two Distinct Model Systems

Abstract: In a host of neurodegenerative diseases Tau, a microtubuleassociated 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 culture… Show more

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Cited by 28 publications
(18 citation statements)
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“…Although oligomer formation has been linked to toxicity in some biological models (73), the physical characteristics of inhibitor-stabilized oligomers differs (24). Consistent with this hypothesis, treatment of brain slices with cyanine inhibitor did not induce apoptotic responses at the low concentrations needed to clear aggregates (10,72). Second, it supports interaction with both 3R and 4R isoforms as well as missense tauopathy mutants, suggesting it could be broadly applicable to both AD and frontotemporal lobar degeneration diseases.…”
Section: Discussionsupporting
confidence: 53%
See 1 more Smart Citation
“…Although oligomer formation has been linked to toxicity in some biological models (73), the physical characteristics of inhibitor-stabilized oligomers differs (24). Consistent with this hypothesis, treatment of brain slices with cyanine inhibitor did not induce apoptotic responses at the low concentrations needed to clear aggregates (10,72). Second, it supports interaction with both 3R and 4R isoforms as well as missense tauopathy mutants, suggesting it could be broadly applicable to both AD and frontotemporal lobar degeneration diseases.…”
Section: Discussionsupporting
confidence: 53%
“…First, it can act at physiologically relevant bulk Tau concentrations. Indeed, cyanine inhibitors have been reported to depress Tau aggregation in ex vivo mouse models of tauopathy (10,72). Although oligomer formation has been linked to toxicity in some biological models (73), the physical characteristics of inhibitor-stabilized oligomers differs (24).…”
Section: Discussionmentioning
confidence: 99%
“…If toxicity were based on interactions of amyloidogenic Tau with other cell components, this might be rescued by enhancing degradation (autophagy, proteasome). Alternatively, if aggregation were the toxic principle, neurons might be detoxified by aggregation inhibitors, and indeed this has been demonstrated in vitro and in cell models (Pickhardt et al, 2007;Congdon et al, 2009). …”
Section: Discussionmentioning
confidence: 99%
“…Pathology-related PTMs of tau, such as hyperphosphorylation, further decrease the aptitude of N744 as a tau anti-aggregation agent [240]. A similar biphasic behavior is shown by other cyanines [241,242] in cellular models of tau aggregation characterized by mutant and WT tau isoforms [243]. Multivalent, macrocyclic benzothiazoliumbenzothiazole cyanines connected through their N atoms (e.g., 6.32, Figure 6.11) are stronger tau aggregation inhibitors due to multivalency [244,245].…”
Section: Interfering With (Neuro)toxic Tau Species In the Aggregationmentioning
confidence: 82%