Tau-aggregation inhibitor therapy for Alzheimer's disease

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.

Identification of the Tau phosphorylation pattern that drives its aggregation

“…Although earlier work with recombinant Tau phosphorylated by a rat brain extract suggested this posttranslational modification (PTM) is sufficient to promote fiber formation (16), the Tau aggregation inhibitor methylene blue was discovered in an assay independent of this PTM (17,18). Its clinical failure underscores that further knowledge of the aggregation process is still required.…”

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

“…Tau aggregates have been targeted using several approaches, which have been reviewed elsewhere [29,30]. In the last decade, different classes of tau aggregation inhibitors (TAIs) have been reported, including polyphenols [31], porphyrins [32], phenothiazines such as Methylene blue [32], benzothiazoles/cyanines such as N744 and Riluzole [33], thioxothiazolidinones (rhodanines), phenylthiazolehydrazides, anthraquinones, and aminothienopyridazines (ATPZs) [30,33] (Table 2).…”

“…Furthermore, small molecules belonging to TAIs have already been developed and tested in humans [29,34,35], even if with discrepancy between the cell-based and/or in vitro data and the in vivo efficacy. Important pharmaceutical implications have been rising from the possibility to distinguish the tau-tau binding interaction from the tautubulin binding one with new aggregation inhibitors [36,37].…”

“…Important pharmaceutical implications have been rising from the possibility to distinguish the tau-tau binding interaction from the tautubulin binding one with new aggregation inhibitors [36,37]. Among these, the most promising compound is leucomethylthioninium (LMT, leucomethylene blue (MB), LMTX, TRx0237), developed by TauRxTherapeutics Ltd., Republic of Singapore, which is a secondgeneration TAI for AD treatment.…”

Radiation and Alzheimer's Disease (AD)

“…Intranasal inhalation of radon gas could subject the rhinencephalon and hippocampus to damaging radiation that initiated AD [8]. The Alzheimer neurofibrillary tangle is composed of tau, which is one of the most common pathological hallmarks of AD and tau aggregation pathology at Braak stage 1 1 (out of 6 Braak stages) or beyond affects 50% of the population over the age of 45 [9][10][11]. Our recent review of the effect of the pre-and post-natal irradiation on animal models and human studies indicated many similarities in hippocampal neuropathology, cognitive impairment and relevant molecular mechanisms between Alzheimer's disease and early life radiation exposure-induced neuropsychological disorders [12][13][14][15][16].…”