A tetra(ethylene glycol) derivative of benzothiazole aniline ameliorates dendritic spine density and cognitive function in a mouse model of Alzheimer's disease

Abstract

We recently reported that the tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, acts as an amyloid-binding small molecule that promotes dendritic spine density and cognitive function in wild-type mice. This raised the possibility that BTA-EG4 may benefit the functional decline seen in Alzheimer's disease (AD). In the present study, we directly tested whether BTA-EG4 improves dendritic spine density and cognitive function in a well-established mouse model of AD carrying mutations in APP, PS1 and tau (APPswe;PS1M146V;tauP301L, 3xTg AD mice). We found that daily injections of BTA-EG4 for 2weeks improved dendritic spine density and cognitive function of 3xTg AD mice in an age-dependent manner. Specifically, BTA-EG4 promoted both dendritic spine density and morphology alterations in cortical layers II/III and in the hippocampus at 6–10months of age compared to vehicle-injected mice. However, at 13–16months of age, only cortical spine density was improved without changes in spine morphology. The changes in dendritic spine density correlated with Ras activity, such that 6–10month old BTA-EG4 injected 3xTg AD mice had increased Ras activity in the cortex and hippocampus, while 13–16month old mice only trended toward an increase in Ras activity in the cortex. Finally, BTA-EG4 injected 3xTg AD mice at 6–10months of age showed improved learning and memory; however, only minimal improvement was observed at 13–16months of age. This behavioral improvement corresponds to a decrease in soluble Aβ 40 levels. Taken together, these findings suggest that BTA-EG4 may be beneficial in ameliorating the synaptic loss seen in early AD.