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

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 (APP_swe;PS1_M146V;tau_P301L, 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.