Disaggregation of tau as a therapeutic approach to tauopathies.
Tau aggregation is an appealing target for therapeutic intervention. However, conformational change or aggregation needs to be targeted without inhibiting the normal biology of tau and its role in microtubule stabilization. The number of compound classes being tested at this time are very limited and include Congo red derivatives [2], anthraquinones (Pickhardt et al. 2005 [3], disputed in Crowe et al. 2007 [4]), 2,3-di(furan-2-yl)-quinoxalines , phenylthiazolyl-hydrazide (PTH) [5], polyphenols and porphyrins [6] and cyanine dyes [1, 7, 8]. Herein we have utilized a member of the cyanine dye family (C11) in an organotypic slice culture model of tangle formation. Our results demonstrate that C11 is capable of affecting tau polymerization in a biphasic, dose dependent manner. At submicromolar concentrations (0.001 microM) C11 reduced levels of aggregated tau. However, higher doses resulted in an increase in tau polymerization. These effects can also be seen at the level of individual filaments with changes in filament length and number mirroring the pattern seen via immunoblotting. In addition, this effect is achieved without altering levels of phosphorylation at disease and microtubule binding relevant epitopes.
Duff
K
K
Taub Institute / Department of Pathology, Columbia University and Dept of Integrative Neuroscience, New York State Psychiatric Institute, New York, USA. ked2115@columbia.edu
Kuret
J
J
Congdon
E E
EE
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002232:Carbocyanines / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000187:drug effects* / Q000378:metabolism*; D009924:Organ Culture Techniques; D011108:Polymers / Q000737:chemistry; D013329:Structure-Activity Relationship; D024801:Tauopathies / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism*
D002232:Carbocyanines; D011108:Polymers; C505137:cyanine dye N744; D016875:tau Proteins