Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
College of Pharmacy, Seoul National University, South Korea.
Exp Neurol. 2014 Feb;252:105-13. doi: 10.1016/j.expneurol.2013.11.023. Epub 2013 Dec 6.
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 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 soluble Aβ 40 levels. Taken together, these findings suggest that BTA-EG4 may be beneficial in ameliorating the synaptic loss seen in early AD.
我们最近报道称，苯并噻唑苯胺的四（乙二醇）衍生物 BTA-EG4 可作为一种淀粉样蛋白结合小分子，可促进野生型小鼠树突棘密度和认知功能。这就提出了一种可能性，即 BTA-EG4 可能有益于改善阿尔茨海默病（AD）中出现的功能下降。在本研究中，我们直接测试了 BTA-EG4 是否可以改善携带 APP、PS1 和 tau 突变的 AD 小鼠模型（APPswe；PS1M146V；tauP301L，3xTg AD 小鼠）中的树突棘密度和认知功能。我们发现，BTA-EG4 的每日注射可改善 3xTg AD 小鼠的树突棘密度和认知功能，这种改善具有年龄依赖性。具体而言，与载体注射的小鼠相比，BTA-EG4 在 6-10 个月龄时促进了皮质层 II/III 和海马中的树突棘密度和形态改变。然而，在 13-16 个月龄时，仅改善了皮质突密度，而突棘形态没有变化。树突棘密度的变化与 Ras 活性相关，即 6-10 个月龄 BTA-EG4 注射的 3xTg AD 小鼠的皮质和海马中的 Ras 活性增加，而 13-16 个月龄的小鼠仅在皮质中的 Ras 活性增加。最后，6-10 个月龄 BTA-EG4 注射的 3xTg AD 小鼠表现出学习和记忆能力的改善；然而，仅在 13-16 个月龄时观察到最小的改善。这种行为改善与可溶性 Aβ40 水平的降低有关。总之，这些发现表明，BTA-EG4 可能有益于改善 AD 早期的突触丢失。
