Tau-aggregation inhibitors for the treatment of Alzheimer's disease: the time for Tau is now

Alzheimer’s disease (AD) is an irreversible, neurodegenerative disorder characterized by the progressive loss of memory and thinking skills. There are currently two main hypotheses regarding the cause of dementia in AD: the Ab cascade hypothesis based on aggregation of extracellular Aβ, and the tau aggregation hypothesis based on intracellular tau aggregates. The neurofibrillary tangle is composed of tau protein, and tau aggregation in the brain is directly linked to clinical dementia. The clinic-pathological correlations, strongly supported by the genetic evidence for a primary role for tau protein aggregation in a wide range of neurodegenerative disorders led to the inference that a drug which blocks the aberrant tau binding interaction which is necessary for aggregation could have beneficial effects in the treatment of AD.
To establish the validity of the tau aggregation hypothesis, we have developed tau-transgenic animal models and demonstrate that tau aggregation on its own is sufficient to produce cognitive and other behavioural defects, and that blocking tau aggregation reverses these defects. Diaminophenothiazines were identified as a class of pharmaceutically viable compounds inhibiting selectively tau-tau aggregation in vitro and in vivo without affecting the normal tau-tubulin interaction. Our findings show that the substances, MTC (rember™) and the follow-up molecule LMTX™, a compound with a more enhanced efficacy profile, both act as Tau-Aggregation-Inhibitors (TAIs) in the transgenic mouse models. This provides prominent support to the rationale for treating AD using TAI therapy, and after MTC had successfully passed a phase 2 clinical trial, LMTX™ now has entered worldwide, including Singapore, into phase 3 clinical trials to treat behavioural variant Frontotemporal Dementia (bvFTD) and AD, two neurodegenerative diseases where a prominent tau pathology is observed.