1 Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China.
2 Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
Brain. 2016 Mar;139(Pt 3):908-21. doi: 10.1093/brain/awv383. Epub 2016 Jan 20.
The cholinergic nucleus basalis of Meynert, which is important for memory functions, shows neuronal activation ('up-phase') during the early stages of Alzheimer's disease and neurodegeneration ('down-phase') in later stages of Alzheimer's disease. MicroRNA-132 (miR-132) and the transcription factor early growth response-1 (EGR1) were proposed as possible candidate molecules regulating such an up-down activity pattern of the nucleus basalis of Meynert during the course of Alzheimer's disease, as they both show this up-down pattern of expression in the prefrontal cortex during the course of Alzheimer's disease. Not only do these two molecules stimulate synaptic activity and plasticity, they are also involved in Alzheimer's disease pathology and might, in addition, affect cholinergic function. In the nucleus basalis of Meynert, we investigated the expression of miR-132 and EGR1 along the entire course of Alzheimer's disease. Forty-nine post-mortem nucleus basalis of Meynert samples were studied, ranging from non-demented controls (Braak stage = 0) to late Alzheimer's disease patients (Braak stage = VI), and from clinical Reisberg scale 1 to 7. Each Braak stage contained seven samples, that were all well matched for confounding factors, i.e. age (range 58-91), sex, post-mortem delay, cerebrospinal fluid pH (as a measure for agonal state), APOE genotype, clock time of death, tissue fixation time, and tissue storage time. The alterations of these two molecules were studied over the course of Alzheimer's disease in relation to the expression of 4G8-stained amyloid-β, hyperphosphorylated tau stained by antibody AT8, neuronal fibrillary tangles and neuropil threads stained by silver, and in relation to alterations in choline acetyltransferase. We found that the expression of miR-132 and EGR1 in the nucleus basalis of Meynert was quite stable during the early stages of Alzheimer's disease and decreased significantly only during late Alzheimer's disease stages. In addition, miR-132 and EGR1 showed a significant positive correlation with choline acetyltransferase expression (r = 0.49, P < 0.001 and r = 0.61, P < 0.001), while choline acetyltransferase expression showed a significantly negative correlation with hyperphosphorylated tau (r = -0.33, P = 0.021) but no correlation with 4G8-stained amyloid-β. From the functional changes of miR-132 and EGR1 along the course of Alzheimer's disease we conclude: (i) that these two molecules may play a role in keeping the cholinergic function intact in early Alzheimer's disease stages; and (ii) that these molecules may contribute to the late neurodegeneration of this cholinergic nucleus.
基底前脑胆碱能核团梅内尔特，对记忆功能很重要，在阿尔茨海默病的早期阶段显示神经元激活（“上升阶段”），在阿尔茨海默病的后期阶段显示神经退行性变（“下降阶段”）。microRNA-132 (miR-132) 和早期生长反应因子 1 (EGR1) 被提议作为可能的候选分子，调节梅内尔特基底前脑在阿尔茨海默病过程中的这种上升-下降活动模式，因为它们在阿尔茨海默病过程中都表现出这种上升-下降的表达模式。这两种分子不仅刺激突触活动和可塑性，还参与阿尔茨海默病的病理学，并且可能会影响胆碱能功能。在梅内尔特基底前脑，我们研究了 miR-132 和 EGR1 在整个阿尔茨海默病过程中的表达情况。研究了 49 个死后梅内尔特基底前脑样本，范围从无痴呆对照（Braak 阶段=0）到晚期阿尔茨海默病患者（Braak 阶段=VI），从临床 Reisberg 量表 1 到 7。每个 Braak 阶段包含 7 个样本，所有样本均经过混杂因素的良好匹配，即年龄（范围 58-91）、性别、死后延迟、脑脊液 pH（作为濒死状态的指标）、APOE 基因型、死亡时钟时间、组织固定时间和组织储存时间。研究了这两种分子的变化与 4G8 染色的淀粉样β、由抗体 AT8 染色的过度磷酸化 tau、由银染色的神经元纤维缠结和神经丝之间的关系，并与胆碱乙酰转移酶的变化有关。我们发现，miR-132 和 EGR1 在梅内尔特基底前脑的表达在阿尔茨海默病的早期阶段相当稳定，仅在阿尔茨海默病的晚期阶段才显著下降。此外，miR-132 和 EGR1 与胆碱乙酰转移酶的表达呈显著正相关（r=0.49，P<0.001 和 r=0.61，P<0.001），而胆碱乙酰转移酶的表达与过度磷酸化 tau 呈显著负相关（r=-0.33，P=0.021），但与 4G8 染色的淀粉样β无相关性。从 miR-132 和 EGR1 在阿尔茨海默病过程中的功能变化中我们得出结论：（i）这两种分子可能在阿尔茨海默病早期阶段维持胆碱能功能完整方面发挥作用；（ii）这些分子可能导致该胆碱能核团的晚期神经退行性变。
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