In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

Abstract

Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer's disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.

Constant Levels of Tau Phosphorylation in the Brain of htau Mice

“…Almost all of these studies started treatment in young htau mice and evaluated the effect in old animals or even used old mice from the beginning on ( Ma et al, 2013 ; Congdon et al, 2016 ; Maphis et al, 2016 ; Giannopoulos et al, 2018 ; Brendel et al, 2019 ). Only in two studies treatment of htau mice started before the age of 4 months and evaluated compound effects before the age of 6.5 months ( Garwood et al, 2010 ; Davidowitz et al, 2020 ). Garwood and colleagues were able to reduce cortical pro-inflammatory cytokines in htau mice by treating 3–4 month old htau mice for only 14 days with minocycline and thus showing that the pathology of htau mice can be improved by early treatment.…”

Comprehensive Review on Alzheimer’s Disease: Causes and Treatment

“…Davidowitz et al utilized the hatu mouse model of tauopathy to study the efficacy of a lead small molecule in preventing tau accumulation. The study results demonstrated a significant reduction in tau levels and its phosphorylated form levels, which indicates the ability to inhibit the entire pathway of the tau aggregation by using an optimized lead compound [ 128 ].…”

Disentangling tau: One protein, many therapeutic approaches

“…A phase II trial in patients with MCI showed that it was well tolerated with a potential signal on efficacy; however, the compound was not pursued further [ 83 ]. Another microtubular stabilizer, epothilone D, improved cognitive performance in the PS19 tauopathy mouse model, even when the compound was given after the development of tau tangles and cognitive deficits had already occurred [ 84 ]. This compound did not progress past phase I.…”

“…OLX-07010 is a small molecule that was identified in high-throughput screen for compounds that block the self-association of full-length, non-mutated tau. In nonclinical models, OLX-07010 reduced tau hyperphosphorylation in htau mice [ 84 ]. The compound will start phase I trials in healthy volunteers this fall.…”