Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 20218, USA.
J Neurosci. 2013 May 29;33(22):9306-18. doi: 10.1523/JNEUROSCI.1615-12.2013.
The tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, is a novel amyloid-binding small molecule that can penetrate the blood-brain barrier and protect cells from Aβ-induced toxicity. However, the effects of Aβ-targeting molecules on other cellular processes, including those that modulate synaptic plasticity, remain unknown. We report here that BTA-EG4 decreases Aβ levels, alters cell surface expression of amyloid precursor protein (APP), and improves memory in wild-type mice. Interestingly, the BTA-EG4-mediated behavioral improvement is not correlated with LTP, but with increased spinogenesis. The higher dendritic spine density reflects an increase in the number of functional synapses as determined by increased miniature EPSC (mEPSC) frequency without changes in presynaptic parameters or postsynaptic mEPSC amplitude. Additionally, BTA-EG4 requires APP to regulate dendritic spine density through a Ras signaling-dependent mechanism. Thus, BTA-EG4 may provide broad therapeutic benefits for improving neuronal and cognitive function, and may have implications in neurodegenerative disease therapy.
苯并噻唑苯胺的四（乙二醇）衍生物 BTA-EG4 是一种新型的淀粉样蛋白结合小分子，能够穿透血脑屏障并保护细胞免受 Aβ 诱导的毒性。然而，针对 Aβ 的靶向分子对其他细胞过程的影响，包括调节突触可塑性的过程，仍然未知。我们在这里报告，BTA-EG4 降低 Aβ 水平，改变淀粉样前体蛋白（APP）的细胞表面表达，并改善野生型小鼠的记忆。有趣的是，BTA-EG4 介导的行为改善与 LTP 无关，而是与 spinogenesis 增加有关。较高的树突棘密度反映了功能性突触数量的增加，这是通过增加微小 EPSC（mEPSC）频率来确定的，而突触前参数或突触后 mEPSC 幅度没有变化。此外，BTA-EG4 通过 Ras 信号依赖性机制需要 APP 来调节树突棘密度。因此，BTA-EG4 可能为改善神经元和认知功能提供广泛的治疗益处，并可能对神经退行性疾病的治疗具有重要意义。
