%0 Journal Article %1 RN61 %A Navarrete, L.P. %A Guzman, L. %A San Martin, A. %A Astudillo-Saavedra, L. %A Maccioni, R.B. %D 2012 %J Journal of Alzheimers Disease %K acid aggregates, alzheimer's anti-alzheimer's binding, dementia, derivatives, disease, diseases, dqcauchile filament filaments, helical molecules, neurodegenerative paired parkinsons-disease, potential protein protein-tau, quinolines, structures, tau tubulin, %N 1 %P 79-88 %R 10.3233/Jad-2011-110995 %T Molecules of the Quinoline Family Block Tau Self-Aggregation: Implications toward a Therapeutic Approach for Alzheimer's Disease %U /brokenurl#<Go to ISI>://WOS:000301139000007 %V 29 %X The neurofibrillary tangles (NFTs) generated by self-aggregation of anomalous forms of tau represent a neuropathological hallmark of Alzheimer's disease (AD). These lesions begin to form long before the clinical manifestation of AD, and its severity is correlated with cognitive impairment in patients. We focused on the search for molecules that interact with aggregated tau of the Alzheimer's type and that may block its aggregation before the formation of NFTs. We show that molecules from a family of quinolines interact specifically with oligomeric forms of tau, inhibiting their assembly into AD filaments. The quinolines 2-(4-methylphenyl)-6-methyl quinoline (THQ-4S) and 2-(4-aminophenyl)-6-methylquinoline (THQ-55) inhibited in vitro aggregation of heparin-induced polymers of purified brain tau and aggregates of human recombinant tau. They also interact with paired helical filaments (PHFs) purified from AD postmortem brains. In vitro studies indicated a significantly lower inhibitory effect of amyloid-beta(42) on the aggregation, suggesting that tau aggregates are specific targets for quinoline interactions. These compounds showed highly lipophilic properties as corroborated with the analysis of total polar surface areas, and evaluation of their molecular properties. Moreover, these quinolines exhibit physical chemical properties similar to drugs able to penetrate the human brain blood barrier. Docking studies based on tau modeling, as a structural approach to the analysis of the interaction of tau-binding ligands, indicated that a C-terminal tau moiety, involved in the formation of PHFs, seems to be a site for binding of quinolines. Studies suggest the potential clinical use of these quinolines and of their derivatives to inhibit tau aggregation and possible therapeutic routes for AD.

@article{RN61, abstract = {The neurofibrillary tangles (NFTs) generated by self-aggregation of anomalous forms of tau represent a neuropathological hallmark of Alzheimer's disease (AD). These lesions begin to form long before the clinical manifestation of AD, and its severity is correlated with cognitive impairment in patients. We focused on the search for molecules that interact with aggregated tau of the Alzheimer's type and that may block its aggregation before the formation of NFTs. We show that molecules from a family of quinolines interact specifically with oligomeric forms of tau, inhibiting their assembly into AD filaments. The quinolines 2-(4-methylphenyl)-6-methyl quinoline (THQ-4S) and 2-(4-aminophenyl)-6-methylquinoline (THQ-55) inhibited in vitro aggregation of heparin-induced polymers of purified brain tau and aggregates of human recombinant tau. They also interact with paired helical filaments (PHFs) purified from AD postmortem brains. In vitro studies indicated a significantly lower inhibitory effect of amyloid-beta(42) on the aggregation, suggesting that tau aggregates are specific targets for quinoline interactions. These compounds showed highly lipophilic properties as corroborated with the analysis of total polar surface areas, and evaluation of their molecular properties. Moreover, these quinolines exhibit physical chemical properties similar to drugs able to penetrate the human brain blood barrier. Docking studies based on tau modeling, as a structural approach to the analysis of the interaction of tau-binding ligands, indicated that a C-terminal tau moiety, involved in the formation of PHFs, seems to be a site for binding of quinolines. Studies suggest the potential clinical use of these quinolines and of their derivatives to inhibit tau aggregation and possible therapeutic routes for AD.}, added-at = {2019-12-04T03:57:35.000+0100}, author = {Navarrete, L.P. and Guzman, L. and San Martin, A. and Astudillo-Saavedra, L. and Maccioni, R.B.}, biburl = {https://www.bibsonomy.org/bibtex/24cb968e5d6d7a889430e6deb9782384f/dqcauchile}, doi = {10.3233/Jad-2011-110995}, interhash = {1a9127ab2d59198f077befb8bbd5462b}, intrahash = {4cb968e5d6d7a889430e6deb9782384f}, issn = {1387-2877}, journal = {Journal of Alzheimers Disease}, keywords = {acid aggregates, alzheimer's anti-alzheimer's binding, dementia, derivatives, disease, diseases, dqcauchile filament filaments, helical molecules, neurodegenerative paired parkinsons-disease, potential protein protein-tau, quinolines, structures, tau tubulin,}, number = 1, pages = {79-88}, timestamp = {2019-12-04T03:58:17.000+0100}, title = {Molecules of the Quinoline Family Block Tau Self-Aggregation: Implications toward a Therapeutic Approach for Alzheimer's Disease}, type = {Journal Article}, url = {/brokenurl#<Go to ISI>://WOS:000301139000007}, volume = 29, year = 2012 }