Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University, Moorenstr.5, 40225, Düsseldorf, Germany.
Acta Neuropathol Commun. 2020 Mar 5;8(1):26. doi: 10.1186/s40478-020-00907-8.
Despite ongoing research efforts, mechanisms of brain aging are still enigmatic and need to be elucidated for a better understanding of age-associated cognitive decline. The aim of this study is to investigate aging in the prefrontal cortex region of human brain in a meta-analysis of transcriptome datasets. We analyzed 591 gene expression datasets pertaining to female and male human prefrontal cortex biopsies of distinct ages. We used hierarchical clustering and principal component analysis (PCA) to determine the influence of sex and age on global transcriptome levels. In sex-specific analysis we identified genes correlating with age and differentially expressed between groups of young, middle-aged and aged. Pathways and gene ontologies (GOs) over-represented in the resulting gene sets were calculated. Potential causal relationships between genes and between GOs were explored employing the Granger test of gene expression time series over the range of ages. The most outstanding results were the age-related decline of synaptic transmission and activated expression of glial fibrillary acidic protein (GFAP) in both sexes. We found an antagonistic relationship between calcium/calmodulin dependent protein kinase IV (CAMK4) and GFAP which may include regulatory mechanisms involving cAMP responsive element binding protein (CREB) and mitogen-activated protein kinase (MAPK, alias ERK). Common to both sexes was a decline in synaptic transmission, neurogenesis and an increased base-level of inflammatory and immune-related processes. Furthermore, we detected differences in dendritic spine morphogenesis, catecholamine signaling and cellular responses to external stimuli, particularly to metal (Zinc and cadmium) ions which were higher in female brains.
尽管研究工作一直在进行，但大脑衰老的机制仍然很神秘，需要进一步阐明，以便更好地理解与年龄相关的认知能力下降。本研究旨在通过对转录组数据集的荟萃分析来研究人类大脑前额叶皮层的衰老。我们分析了 591 个与女性和男性前额叶皮层活检不同年龄相关的基因表达数据集。我们使用层次聚类和主成分分析 (PCA) 来确定性别和年龄对整体转录组水平的影响。在性别特异性分析中，我们确定了与年龄相关并在年轻、中年和老年组之间差异表达的基因。计算了由此产生的基因集中相关的途径和基因本体 (GO)。利用基因表达时间序列在年龄范围内的格兰杰因果检验，探索了基因之间和 GO 之间的潜在因果关系。最显著的结果是两性中突触传递的年龄相关性下降和神经胶质纤维酸性蛋白 (GFAP) 的激活表达。我们发现钙/钙调蛋白依赖性蛋白激酶 IV (CAMK4) 和 GFAP 之间存在拮抗关系，其中可能包括涉及环磷酸腺苷反应元件结合蛋白 (CREB) 和丝裂原激活蛋白激酶 (MAPK，又名 ERK) 的调节机制。两性共有的是突触传递、神经发生和炎症及免疫相关过程基础水平增加。此外，我们检测到树突棘形态发生、儿茶酚胺信号和细胞对外界刺激的反应的差异，特别是女性大脑中锌和镉等金属离子的反应差异更大。
