Badin Antoine-Scott, Morrill Paul, Devonshire Ian M, Greenfield Susan A
Neuro-Bio Ltd, Building F5, Culham Science Centre, Oxfordshire, OX14 3DB, United Kingdom.
Neuro-Bio Ltd, Building F5, Culham Science Centre, Oxfordshire, OX14 3DB, United Kingdom.
Neuropharmacology. 2016 Jun;105:47-60. doi: 10.1016/j.neuropharm.2016.01.012. Epub 2016 Jan 7.
Previous studies have suggested that neurodegeneration is an aberrant form of development, mediated by a novel peptide from the C-terminus of acetylcholinesterase (AChE). Using voltage-sensitive dye imaging we have investigated the effects of a synthetic version of this peptide in the in vitro rat basal forebrain, a key site of degeneration in Alzheimer's disease. The brain slice preparation enables direct visualisation in real-time of sub-second meso-scale neuronal coalitions ('Neuronal Assemblies') that serve as a powerful index of brain functional activity. Here we show that (1) assemblies are site-specific in their activity profile with the cortex displaying a significantly more extensive network activity than the sub-cortical basal forebrain; (2) there is an age-dependency, in both cortical and sub-cortical sites, with the younger brain (p14 rats) exhibiting more conspicuous assemblies over space and time compared to their older counterparts (p35-40 rats). (3) AChE-derived peptide significantly modulates the dynamics of neuronal assemblies in the basal forebrain of the p14 rat with the degree of modulation negatively correlated with age, (4) the differential in assembly size with age parallels the level of endogenous peptide in the brain, which also declines with maturity, and (5) this effect is completely reversed by a cyclised variant of AChE-peptide, 'NBP14'. These observations are attributed to an enhanced calcium entry that, according to developmental stage, could be either trophic or toxic, and as such may provide insight into the basic neurodegenerative process as well as an eventual therapeutic intervention.
先前的研究表明，神经退行性变是一种异常的发育形式，由乙酰胆碱酯酶（AChE）C末端的一种新型肽介导。我们使用电压敏感染料成像技术，研究了这种肽的合成版本对体外大鼠基底前脑（阿尔茨海默病中一个关键的退化部位）的影响。脑片制备能够实时直接可视化亚秒级中尺度神经元联合体（“神经元集合”），这些联合体是大脑功能活动的有力指标。在这里，我们表明：（1）联合体在其活动模式上具有位点特异性，皮层显示出比皮层下基底前脑更广泛的网络活动；（2）在皮层和皮层下位点都存在年龄依赖性，与年龄较大的对应物（p35 - 40大鼠）相比，年轻大脑（p14大鼠）在空间和时间上表现出更明显的联合体；（3）AChE衍生肽显著调节p14大鼠基底前脑神经元联合体的动力学，调节程度与年龄呈负相关；（4）联合体大小随年龄的差异与大脑中内源性肽的水平平行，内源性肽水平也随成熟而下降；（5）AChE肽的环化变体“NBP14”完全逆转了这种效应。这些观察结果归因于钙内流增强，根据发育阶段，钙内流可能是营养性的或毒性的，因此可能为基本的神经退行性变过程以及最终的治疗干预提供见解。
