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 ADcarrying mutations in APP, PS1 and tau (APPswe;PS1M146V;tauP301L, 3xTg AD mice). We found that daily injections of BTA-EG4 for 2 weeks 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 6–10 months of age compared to vehicle-injected mice. However, at 13–16 months 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 6–10 month old BTA-EG4 injected 3xTg AD mice had increased Ras activity in the cortex and hippocampus, while 13–16 month old mice only trended toward an increase in Ras activity in the cortex. Finally, BTA-EG4 injected 3xTg AD mice at 6–10 months of age showed improved learning and memory; however, only minimal improvement was observed at 13–16 months of age. This behavioral improvement corresponds to a decrease in Aβ levels. Taken together, these findings suggest that BTA-EG4 may be beneficial in ameliorating the synaptic loss seen in early AD.

Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

“…Previous work has reported that BTA-EG 4 and BTA-EG 6 could promote spine density increases in vitro in murine primary hippocampal neurons (37) and BTA-EG 4 could promote spine density increases in vivo in the hippocampus of wt mice and a 3ϫ tg mouse model for AD (18,19). The increase in spine density in neurons by BTA-EG 4,6 correlated with an increase in expression of RasGRF1 compared with control cells (37).…”

“…In conclusion, we used rational design to develop a novel set of benzothiazole amphiphiles 1-3 with improved biocompatibility compared with the previously reported BTA-EG 4,6 compounds (17)(18)(19). These new compounds were capable of 1) promoting dose-dependent increases in dendritic spine density, 2) temporally and reversibly controlling elevated spine levels, and 3) protecting against A␤-induced dendritic spine loss.…”

“…We previously reported the design, synthesis, and evaluation of two oligo(ethylene glycol) derivatives of benzothiazole aniline (BTA), BTA-EG 6 and BTA-EG 4 , which exhibited a variety of advantageous properties for the potential treatment of neurodegenerative diseases such as AD (17)(18)(19). Interestingly, BTA-EG 4 showed the capability to improve memory and learning in cognitive performance tests in both wild-type mice and in a mouse model for AD (18,19).…”

“…Interestingly, BTA-EG 4 showed the capability to improve memory and learning in cognitive performance tests in both wild-type mice and in a mouse model for AD (18,19). This in vivo activity of BTA-EG 4 was also accompanied by a phenotypic increase in dendritic spine density (18,19). Because of the scarcity of small molecules known to increase dendritic spine density, this rare feature of benzothiazole amphiphiles is of particular interest and could be utilized as a tool to help study the relationship between spines and cognitive function.…”

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

“…A possible explanation for this observation is that catalase ameliorates Aβ toxicity via two independent ways, firstly it decreases elevated ROS levels and secondly that it acts as a scavenger of Aβ and the latter function is blocked by BTA-EG 4 [173]. However, the latest study demonstrated that BTA-EG 4 produces an age-specific improvement in synaptic density and cognitive function in an AD mouse model, when administered daily for two weeks and an associated change in dendritic spine density with increased Ras activity [174]. Additionally, polyphenol phloroglucinol ( Fig.…”