Tau-aggregation inhibitor therapy for Alzheimer's disease

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Abstract

Many trials of drugs aimed at preventing or clearing β-amyloid pathology have failed to demonstrate efficacy in recent years and further trials continue with drugs aimed at the same targets and mechanisms. The Alzheimer neurofibrillary tangle is composed of tau and the core of its constituent filaments are made of a truncated fragment from the repeat domain of tau. This truncated tau can catalyse the conversion of normal soluble tau into aggregated oligomeric and fibrillar tau which, in turn, can spread to neighbouring neurons. Tau aggregation is not a late-life process and onset of Braak stage 1 peaks in people in their late 40s or early 50s. Tau aggregation pathology at Braak stage 1 or beyond affects 50% of the population over the age of 45. The initiation of tau aggregation requires its binding to a non-specific substrate to expose a high affinity tau-tau binding domain and it is self-propagating thereafter. The initiating substrate complex is most likely formed as a consequence of a progressive loss of endosomal-lysosomal processing of neuronal proteins, particularly of membrane proteins from mitochondria. Mutations in the APP/presenilin membrane complex may simply add to the age-related endosomal-lysosomal processing failure, bringing forward, but not directly causing, the tau aggregation cascade in carriers. Methylthioninium chloride (MTC), the first identified tau aggregation inhibitor (TAI), offers an alternative to the amyloid approach. Phase 3 trials are underway with a novel stabilized reduced form of methylthioninium (LMTX) that has improved tolerability and absorption.

Original languageEnglish
Pages (from-to)529-539
Number of pages11
JournalBiochemical Pharmacology
Volume88
Issue number4
Early online date19 Dec 2013
DOIs
Publication statusPublished - 15 Apr 2014

Fingerprint

Amyloid
Alzheimer Disease
Agglomeration
Presenilins
Pathology
Neurofibrillary Tangles
Methylene Blue
Pharmaceutical Preparations
Mitochondria
Membrane Proteins
Neurons
Mutation
Membranes
Therapeutics
Population
Substrates
Processing
Proteins

Keywords

  • Alzheimer Disease
  • Clinical Trials, Phase II as Topic
  • Humans
  • Phosphorylation
  • tau Proteins
  • Amyloid
  • Methylthioninium
  • Tau

Cite this

Tau-aggregation inhibitor therapy for Alzheimer's disease. / Wischik, Claude M; Harrington, Charles R; Storey, John M D.

In: Biochemical Pharmacology, Vol. 88, No. 4, 15.04.2014, p. 529-539.

Research output: Contribution to journalArticle

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