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J Biol Chem. 2015 Apr 24;290(17):10862-75. doi: 10.1074/jbc.M114.616029. Epub 2015 Mar 10.

Cellular Models of Aggregation-dependent Template-directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer Disease.

Author information

1
From the School of Medicine and Dentistry, University of Aberdeen, Aberdeen AB25 2ZP, United Kingdom, TauRx Therapeutics Ltd., Singapore 068805, and the Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, United Kingdom c.harrington@abdn.ac.uk.
2
TauRx Therapeutics Ltd., Singapore 068805, and the Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, United Kingdom.
3
the Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, United Kingdom.
4
From the School of Medicine and Dentistry, University of Aberdeen, Aberdeen AB25 2ZP, United Kingdom.
5
From the School of Medicine and Dentistry, University of Aberdeen, Aberdeen AB25 2ZP, United Kingdom, TauRx Therapeutics Ltd., Singapore 068805, and cmw@taurx.com.

Abstract

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.

KEYWORDS:

Alzheimer Disease; Cell Biology; LMTX; Methylthioninium; Prion-like Processing; Protein Aggregation; Tau Protein (Tau); Tauopathy

PMID:
25759392
PMCID:
PMC4409250
DOI:
10.1074/jbc.M114.616029
[Indexed for MEDLINE]
Free PMC Article

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