The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology

Abstract

Alzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aβ pores without changing the membrane embedded Aβ‐oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD‐related pathology that should be investigated further.

Anle138b modulates α‐synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy

“…Here we show that anle138b, which targets specifically oligomers, reduces α‐syn accumulation in a mouse model of early‐stage MSA, thus corroborating the oligomer modulation effect on α‐syn previously observed in PD models and the general effect observed also in Abeta, tau, and prion aggregation mouse models . An important advantage of this small molecule, from a therapeutic point of view, is that it does not bind to α‐syn monomers, therefore preserving its physiological functions .…”

“…Thus, administration of anle138b as a food additive results in adequate and stable drug exposure . Anle138b has been shown effective in reducing disease progression in models of PD, prion disease, tauopathy, and Alzheimer's disease (AD) by inhibiting protein aggregation . Based on this, we hypothesized that it could also be of use to attenuate disease progression in MSA.…”

Could blocking the formation of amyloid channels rescue Alzheimer's phenotype?

“…Anle138b was first described as an anti‐oligomeric agent capable of blocking in different mouse models the neurotoxic effects of tau, prion, and α‐synuclein oligomers, which are associated to human tauopathies, prion, and Parkinson's diseases, respectively (Matthes et al , ). Martinez Hernandez et al () now show that Anle138b also interferes with Aβ toxicity. They first observed that Anle138b was able to improve survival times in a Drosophila model of amyloid‐induced neurotoxicity.…”

“…AD patients who received Aducanumab had a decrease in the number of amyloid plaques observed by PET and a slower cognitive decline (Sevigny et al , ), suggesting that therapeutic interventions targeting Aβ could be beneficial. The new study of Martinez Hernandez et al () in the current issue of EMBO Molecular Medicine present solid evidence that the diphenylpyrazole compound Anle138b prevents and reduces the toxic effects of Aβ in a mouse model of AD, giving new hope that attacking Aβ can produce therapeutic benefits. Anle138b was first described as an anti‐oligomeric agent capable of blocking in different mouse models the neurotoxic effects of tau, prion, and α‐synuclein oligomers, which are associated to human tauopathies, prion, and Parkinson's diseases, respectively (Matthes et al , ).…”

“…Anle138b has been shown to inhibit the formation of oligomers formed by several disease‐associated proteins (Matthes et al , ). In order to evaluate whether part of the effect of Anle138b is caused by the interference of Aβ aggregation, Martinez Hernandez et al () analyzed brain sections of APPPS1ΔE9 mice by thioflavin staining which had been previously treated with placebo or Anle138b at the pre‐plaque or post‐plaque stage. The number and the area of amyloid plaques were lower in Anle138b‐treated mice; however, the effect was more pronounced in the pre‐plaque group.…”