Neuroregeneration Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
Brain. 2010 Dec;133(Pt 12):3699-723. doi: 10.1093/brain/awq258. Epub 2010 Oct 1.
Using the Braak staging for neurofibrillary changes as an objective indicator of the progression of Alzheimer's disease, we have performed a systematic search for global gene expression changes in the prefrontal cortex during the course of Alzheimer's disease. In the prefrontal cortex, senile plaques and neurofibrillary changes start to appear around Braak stage III, allowing for the detection of changes in gene expression before, during and after the onset of Alzheimer's disease neuropathology. Two distinct patterns of tightly co-regulated groups of genes were observed: (i) an increase in expression in early Braak stages, followed by a decline in expression in later stages (the UPDOWN clusters; containing 865 genes) and (ii) a decrease in expression in early Braak stages, followed by an increase in expression in later stages (the DOWNUP clusters; containing 983 genes). The most profound changes in gene expression were detected between Braak stages II and III, just before or at the onset of plaque pathology and neurofibrillary changes in the prefrontal cortex. We also observed an increase in intracellular beta amyloid staining from Braak stages I to III and a clear decrease in Braak stages IV to VI. These data suggest a link between specific gene expression clusters and Alzheimer's disease-associated neuropathology in the prefrontal cortex. Gene ontology over-representation and functional gene network analyses indicate an increase in synaptic activity and changes in plasticity during the very early pre-symptomatic stage of the disease. In later Braak stages, the decreased expression of these genes suggests a reduction in synaptic activity that coincides with the appearance of plaque pathology and neurofibrillary changes and the clinical diagnosis of mild cognitive impairment. The interaction of the ApoE genotype with the expression levels of the genes in the UPDOWN and DOWNUP clusters demonstrates that the accelerating role of ApoE-ε4 in the progression of Alzheimer's disease is reflected in the temporal changes in gene expression presented here. Since the UPDOWN cluster contains several genes involved in amyloid precursor protein processing and beta amyloid clearance that increase in expression in parallel with increased intracellular beta amyloid load, just before the onset of plaque pathology in the prefrontal cortex, we hypothesize that the temporally orchestrated increase in genes involved in synaptic activity represents a coping mechanism against increased soluble beta amyloid levels. As these gene expression changes occur before the appearance of Alzheimer's disease-associated neuropathology, they provide an excellent starting point for the identification of new targets for the development of therapeutic strategies aimed at the prevention of Alzheimer's disease.
使用 Braak 神经纤维缠结分期作为阿尔茨海默病进展的客观指标，我们对阿尔茨海默病进程中前额叶皮层的全局基因表达变化进行了系统搜索。在额皮质中，老年斑和神经纤维缠结在 Braak 分期 III 左右开始出现，使得在阿尔茨海默病神经病理学发生之前、期间和之后都能检测到基因表达的变化。观察到两种紧密调控的基因簇模式：（i）在早期 Braak 分期中表达增加，随后在晚期表达下降（UPDOWN 簇；包含 865 个基因）和（ii）在早期 Braak 分期中表达下降，随后在晚期表达增加（DOWNUP 簇；包含 983 个基因）。在 Braak 分期 II 和 III 之间，即前额叶皮层出现斑块病理学和神经纤维缠结之前或之时，基因表达的变化最为显著。我们还观察到从 Braak 分期 I 到 III 时细胞内β淀粉样蛋白染色增加，而 Braak 分期 IV 到 VI 时明显减少。这些数据表明，特定基因表达簇与前额叶皮层中与阿尔茨海默病相关的神经病理学之间存在联系。基因本体论过表达和功能基因网络分析表明，在疾病非常早期的无症状阶段，突触活性增加，可塑性发生变化。在后期的 Braak 分期中，这些基因表达的下降表明突触活性的降低与斑块病理学和神经纤维缠结的出现以及轻度认知障碍的临床诊断相吻合。ApoE 基因型与 UPDOWN 和 DOWNUP 簇中基因表达水平的相互作用表明，ApoE-ε4 在阿尔茨海默病进展中的加速作用反映在本研究中呈现的基因表达的时间变化。由于 UPDOWN 簇包含几个参与淀粉样前体蛋白加工和β淀粉样清除的基因，这些基因的表达与细胞内β淀粉样蛋白负荷的增加平行增加，就在前额叶皮层斑块病理学发生之前，我们假设涉及突触活性的基因的时间协调增加代表了一种应对机制，以应对可溶性β淀粉样蛋白水平的增加。由于这些基因表达变化发生在与阿尔茨海默病相关的神经病理学出现之前，因此它们为识别新的靶点提供了一个很好的起点，这些靶点可用于开发旨在预防阿尔茨海默病的治疗策略。
