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Please use this identifier to cite or link to this item: http://dspace.utalca.cl/handle/1950/9140

Title: Molecules of the Quinoline Family Block Tau Self-Aggregation: Implications Toward a Therapeutic Approach for Alzheimer's Disease
Authors: Navarrete, L.P.
Guzman, L. .
San Martin, A.
Astudillo-Saavedra, L.
Maccioni, R.B.
Issue Date: 2012
Publisher: IOS PRESS
Citation: JOURNAL OF ALZHEIMERS DISEASE Volume: 29 Issue: 1 Pages: 79-88 DOI: 10.3233/JAD-2011-110995
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.
Description: Astudillo-Saavedra, L (Astudillo-Saavedra, Luis). Univ Talca, Organ Synth Lab, Talca, Chile
URI: http://dspace.utalca.cl/handle/1950/9140
ISSN: 1387-2877
Appears in Collections:Artículos en publicaciones ISI - Universidad de Talca

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