RESUMEN
Alzheimer disease (AD) is a degenerative tauopathy characterized by aggregation of Tau protein through the repeat domain to form intraneuronal paired helical filaments (PHFs). We report two cell models in which we control the inherent toxicity of the core Tau fragment. These models demonstrate the properties of prion-like recruitment of full-length Tau into an aggregation pathway in which template-directed, endogenous truncation propagates aggregation through the core Tau binding domain. We use these in combination with dissolution of native PHFs to quantify the activity of Tau aggregation inhibitors (TAIs). We report the synthesis of novel stable crystalline leucomethylthioninium salts (LMTX®), which overcome the pharmacokinetic limitations of methylthioninium chloride. LMTX®, as either a dihydromesylate or a dihydrobromide salt, retains TAI activity in vitro and disrupts PHFs isolated from AD brain tissues at 0.16 µM. The Ki value for intracellular TAI activity, which we have been able to determine for the first time, is 0.12 µM. These values are close to the steady state trough brain concentration of methylthioninium ion (0.18 µM) that is required to arrest progression of AD on clinical and imaging end points and the minimum brain concentration (0.13 µM) required to reverse behavioral deficits and pathology in Tau transgenic mice.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Agregación Patológica de Proteínas/tratamiento farmacológico , Agregación Patológica de Proteínas/metabolismo , Proteínas tau/química , Proteínas tau/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular , Humanos , Azul de Metileno/análogos & derivados , Azul de Metileno/síntesis química , Azul de Metileno/química , Azul de Metileno/farmacología , Ratones , Ratones Transgénicos , Modelos Biológicos , Agregado de Proteínas/efectos de los fármacos , Dominios y Motivos de Interacción de Proteínas , Proteolisis , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMEN
The asymmetric di-aminic compartmental ligand HL5 forms a tetranuclear nickel(II) complex in which the core is assembled from two confacial bioctahedra [Ni...Ni, approximately 2.90 A]; the open faces of the bioctahedra are joined at the O atoms of two mu-cresolato bridges [Ni...Ni, 3.72 A], and the shared faces of the bioctahedra are linked by a tetradentate (mu 4, eta 2)-perchlorate anion and by an unusual tetradentate (mu 4, eta 2)-[H3O2]-bridge.