5 years ago

Tau-aggregation inhibitor therapy for Alzheimer's disease

Tau-aggregation inhibitor therapy for Alzheimer's disease
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.

Publisher URL: www.sciencedirect.com/science

DOI: S0006295213007612

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