Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer’s Disease

Abstract

The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. 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 (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

In search of Alzheimer’s disease treatment methods: trends of clinical trials

“…net) fos fo rili ni mas [37]. Ly gi nant to kio pa ties am þiaus svei kø ir sergan èiø AL as me nø tau bal ty mo kie ká sme ge ny se, nu sta tyta, kad ser gan èiø jø sme ge ny se tau yra 4-5 kar tus dau giau, o ðis skir tu mas su si da ro dël hi per fos fo ri lin to tau [41]. Hiper fos fo ri lin to tau mo liui pri klau so 3-4 kar tus dau giau fos fa to mo liø, ne gu fi zio lo gið kai fos fo ri lin tam bal ty mui [39].…”

“…Ma þë ja hi per fos fo ri lin to tau afi nið ku mas mik ro tu bulëms, jis at si ski ria, to dël dau gë ja in tra ci top laz mi nio tau kie kis [37]. Ci top laz mo je su si da ro tau oli go me rai -nuo dime rø iki ok ta me rø, for muo jan tys ne tir pius fi la men tus, ið ku riø su si da ro neu ro fib ri li niø tin kle liø ðer dis [41]. Dau gë -jant tau, jis stip riau sà vei kau ja su ki tais làs te lës bal ty mais, truk do at lik ti jiems ápras tas funk ci jas, taip pat "ið stu mia" juos ið ápras tø lo ka li za ci jø neu ro nuo se, ka dan gi hi per fosfo ri lin tas tau uþ pil do neu ro no kû nà ir den dri tus [37,39].…”

“…Dau gë -jant tau, jis stip riau sà vei kau ja su ki tais làs te lës bal ty mais, truk do at lik ti jiems ápras tas funk ci jas, taip pat "ið stu mia" juos ið ápras tø lo ka li za ci jø neu ro nuo se, ka dan gi hi per fosfo ri lin tas tau uþ pil do neu ro no kû nà ir den dri tus [37,39]. Be to, ma þë ja si nap siø skai èius [41]. Pro gre suo jant li gai, tau ima sà vei kau ti su re ak ty viais kar bo nilo jun gi niais, dël to su si for muo ja su dë tin ges ni gli kuo ti ga lu ti niai pro duk tai, at spa rûs pro te o li zei, tai gi dar la biau ska ti na ma ag re ga ci ja [39].…”

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

“…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).…”

Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

“…Because of this, preventing tau acetylation is critical for stopping disease onset. Salsalate and methylene blue have both been shown to reduce tau acetylation in pre-clinical models, however the exact mechanism has not been fully elucidated and warrants further investigation [10]. It is likely that these drugs are limiting the expansion of secondary injury cascades following insult.…”