Tau-directed approaches for the treatment of Alzheimer’s disease: focus on leuco-methylthioninium

ABSTRACT

Small molecular weight compounds able to inhibit formation of tau oligomers and fibrils have already been tested for Alzheimer’s disease (AD) treatment. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT⁺). MT chloride (also known as methylene blue) was investigated in a 24-week Phase II study in 321 mild-to-moderate AD patients at the doses of 69, 138, and 228 mg/day. This trial failed to show significant positive effects of MT in the overall patient population. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected patients and cerebral blood flow in mildly affected patients. A follow-up compound (TRx0237) claimed to be more bioavailable and less toxic than MT, is now being developed. Phase III clinical trials on this novel TAI in AD and in the behavioral variant of frontotemporal dementia are underway.

KEYWORDS:

• Alzheimer’s disease
• dementia
• tau protein
• leuco-methylthioninium
• TRx0237
• methylthioninium
• tau aggregation inhibitors
• tau phosphorylation inhibitors
• microtubule-stabilizing agents
• immunotherapy

Financial & competing interests disclosure

This study was supported by “Ministero della Salute”, I.R.C.C.S. Research Program, Ricerca Corrente 2015-2017, Linea n. 2 “Malattie complesse e terapie innovative”, by the “5 x 1000” voluntary contribution, and by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale (PRIN) 2009 Grant 2009E4RM4Z. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The two principal neuropathological hallmarks of AD are SPs and neurofibrillary tangles; the former being mainly composed of β-amyloid peptide and the latter of hyperphosphorylated tau protein.

• Tau pathology in AD is principally characterized by abnormal phosphorylation/hyperphosphorylation of tau proteins, but proteolytic cleavage/truncation, glycosylation, nitration, O-GlcNAcylation, ubiquitination, and other abnormal posttranslational modifications are also responsible for the altered tau structure.

• The exact mechanisms by which tau protein becomes a nonfunctional entity are under debate. Nevertheless, several therapies targeting tau aimed to reduce, stabilize, or prevent aggregation or hyperphosphorylation of the protein are being actively pursued.

• In the current state of anti-tau therapy in humans, it is not clear which conformational state (oligomers or truncated tau or aggregated tau) of this protein should be targeted, how tau protein exerts its toxicity, for how long to treat or immunize it, and at which stage of the disease to intervene.

• Among different tau-based approaches, inhibition of tau aggregation is the most advanced therapeutic strategy for the treatment of AD and other tauopathies. Small-molecular weight compounds developed to inhibit formation of tau oligomers and fibrils by blocking tau–tau aggregation have already reached the clinic

• MTC, commonly known as methylene blue, and its derivatives have generated the most clinical data to date and appear to be a viable option for preventing aggregation of tau.

• MT exists in equilibrium between a reduced (LMT) and an oxidized form (MT+). MTC has been investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD.

• This Phase II trial failed to show significant positive effects of MT in the overall patient population.

• Subgroup analyses has shown that at 24 weeks the dose of 138 mg MT/day improved cognition in moderately affected patients and improved rCBF in mildly affects subjects.

• A derivative of MT (TRx0237) with supposedly improved bioavailability and tolerability has been recently developed. Its clinical potential is being tested in large Phase III studies in mild to moderate AD and in bvFTD.