The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Abstract

Background Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly. Methods To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology. Results CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures. Conclusions The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

Lysine-selective molecular tweezers are cell penetrant and concentrate in lysosomes

“…Tau seeds were prepared from PS19-mouse hippocampal extracts and added to biosensor cells for measurement of intracellular tau aggregation as described previously 19 . CLR16 was added 24 h after seeding.…”

“…Recently, we also found that CLR01 inhibited dose-dependently the prion-like propagation of tau aggregates (tau seeding) in biosensor cells 17 . Moreover, the potential therapeutic effect of CLR01 has been demonstrated in multiple animal models of various proteinopathies including the triple-transgenic mouse model of Alzheimer’s disease (AD) 16 , a rat model of AD 18 , a mouse model of tauopathy 19 , zebrafish 12 , 20 and mouse 15 , 21 models of Parkinson’s disease (PD), a lamprey model of spinal cord injury 22 , and mouse models of transthyretin amyloidosis 14 , desmin-related cardiomyopathy 23 , amyotrophic lateral sclerosis 24 , multiple system atrophy 25 , and the lysosomal-storage disease Sanfilippo syndrome type A 26 .…”

Exophers are components of mammalian cell neurobiology in health and disease

“…During the analysis of tauopathy mouse brains 10 , we noticed rare exophers, similar to those described in c. elegans , which were attached to neuronal bodies via nanotubes (Fig. 1).…”

Glimepiride mitigates tauopathy and neuroinflammation in P301S transgenic mice: role of AKT/GSK3β signaling

“…Thus, SU drugs may have potential In this study, P301S transgenic mice was used which is characterized by development of NFT and tau pathology from 3 months of age and previously showed evident pathology with various staining antibodies against tau protein on similar time plan of our study (Hollerhage et al 2014;Allen et al 2002). These mice demonstrated significant motor impairment, anxiety like behavior, reduced exploration when compared to WT (Watt et al 2020;Sun et al 2020;Di et al 2021;Zampar and Wirths 2021) and exhibit behavioral abnormalities that resemble deficits in human tauopathies (Takeuchi et al 2011).Based on previous studies with this experimental model of tauopathy, tau pathology starts by the third month of age, it then increases till reaching the highest level in 5-6 months, however, by that time animals are totally incapacitated so there is difficulty in behavioral tests assessment (Hollerhage et al 2014). Hence, experiment of the current study started on 3rd month of age and proceeded for 21 days, where we can find evident pathology when sacrificed yet preserving locomotion of the animals and decreasing mortalities.…”