Cellular Models of Aggregation-Dependent Template-Directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer's Disease

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Alzheimer's 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 endpoints, and the minimum brain concentration (0.13 μM) required to reverse behavioral deficits and pathology in tau transgenic mice.

Original languageEnglish
Pages (from-to)10862-10875
Number of pages14
JournalThe Journal of Biological Chemistry
Issue number17
Early online date10 Mar 2015
Publication statusPublished - 24 Apr 2015



  • Alzheimer Disease
  • cell biology
  • protein aggregation
  • tau protein (tau)
  • tauopathy
  • LMTX
  • prion-like processing
  • methylthioninium

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