Department of Physiology, School of Medicine and Trinity College Institute of Neuroscience, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
J Biol Chem. 2012 Oct 5;287(41):34709-21. doi: 10.1074/jbc.M112.350678. Epub 2012 Aug 13.
Aberrant Notch signaling has recently emerged as a possible mechanism for the altered neurogenesis, cognitive impairment, and learning and memory deficits associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in models of AD has emerged as a potential approach to slow the progression of the disease process. Although studies have identified neuroprotective roles for endocannabinoids, there is a paucity of information on modulation of the pro-survival Notch pathway by endocannabinoids. In this study the influence of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol, on the Notch-1 pathway and on its endogenous regulators were investigated in an in vitro model of AD. We report that AEA up-regulates Notch-1 signaling in cultured neurons. We also provide evidence that although Aβ(1-42) increases expression of the endogenous inhibitor of Notch-1, numb (Nb), this can be prevented by AEA and 2-arachidonoylglycerol. Interestingly, AEA up-regulated Nct expression, a component of γ-secretase, and this was found to play a crucial role in the enhanced Notch-1 signaling mediated by AEA. The stimulatory effects of AEA on Notch-1 signaling persisted in the presence of Aβ(1-42). AEA was found to induce a preferential processing of Notch-1 over amyloid precursor protein to generate Aβ(1-40). Aging, a natural process of neurodegeneration, was associated with a reduction in Notch-1 signaling in rat cortex and hippocampus, and this was restored with chronic treatment with URB 597. In summary, AEA has the proclivity to enhance Notch-1 signaling in an in vitro model of AD, which may have relevance for restoring neurogenesis and cognition in AD.
异常的 Notch 信号转导最近被认为是阿尔茨海默病（AD）相关神经发生、认知障碍、学习和记忆缺陷改变的可能机制。最近，在 AD 模型中靶向内源性大麻素系统已成为减缓疾病进展的潜在方法。尽管研究已经确定了内源性大麻素的神经保护作用，但关于内源性大麻素对促生存 Notch 途径的调节知之甚少。在这项研究中，研究了内源性大麻素，即花生四烯酸乙醇胺（AEA）和 2-花生四烯酰甘油，对 AD 体外模型中 Notch-1 途径及其内源性调节剂的影响。我们报告说，AEA 上调培养神经元中的 Notch-1 信号转导。我们还提供证据表明，尽管 Aβ（1-42）增加了 Notch-1 的内源性抑制剂 numb（Nb）的表达，但这可以被 AEA 和 2-花生四烯酰甘油预防。有趣的是，AEA 上调了 Notch-1 途径的γ-分泌酶的组成部分 Nct 的表达，这在 AEA 介导的增强的 Notch-1 信号转导中起着关键作用。AEA 对 Notch-1 信号转导的刺激作用在存在 Aβ（1-42）的情况下仍然存在。发现 AEA 诱导 Notch-1 相对于淀粉样前体蛋白的优先加工，以产生 Aβ（1-40）。衰老，即神经退行性变的自然过程，与大鼠皮质和海马中的 Notch-1 信号转导减少有关，而 URB 597 的慢性治疗可恢复这种信号转导。总之，AEA 有增强 AD 体外模型中 Notch-1 信号转导的倾向，这可能与恢复 AD 中的神经发生和认知有关。
