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首页> 外文期刊>Journal of neuroinflammation >Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study
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Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study

机译：微阵列研究：广泛的先天免疫基因激活伴随大脑衰老，增加了对认知能力下降和神经变性的脆弱性

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Background This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD). Methods In a well-powered microarray study of young (20 to 59?years), aged (60 to 99?years), and AD (74 to 95?years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. Results Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II. Conclusions Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife.
机译：背景技术这项研究对衰老和阿尔茨海默氏病（AD）中免疫/炎症相关基因的大脑基因表达谱进行了系统和全面的分析。方法在一项功能强大的微阵列研究中，对年轻（20至59岁），年龄（60至99岁）和AD（74至95岁）病例进行了研究，评估了海马，内嗅皮层，额回和中央后回。结果出现了一些新颖的概念。首先，免疫/炎症相关基因在认知正常衰老过程中显示出主要的基因表达变化，衰老过程中的基因反应程度远大于AD。在微阵列上查询的759种与免疫相关的探针中，随着年龄的增长，SFG，PCG和HC中约40％的抗体发生了显着改变，其中大多数被上调（64％至86％）。相比之下，向AD过渡时显着改变的免疫/炎症基因却要少得多（约占免疫相关探针组的6％），而基因反应主要限于SFG和HC。第二，尽管衰老或AD，EC中检测到的免疫/炎症基因变化相对较少，尽管EC中的许多基因显示出与其他大脑区域相似的反应趋势。第三，免疫/炎症基因在衰老和AD中经历性别特异性反应模式，其中最明显的差异出现在衰老中。最后，在衰老的大脑中，反映小胶质细胞和血管周围巨噬细胞激活的基因普遍上调，同时当小胶质细胞/巨噬细胞激活减弱时，选择因子（TOLLIP，分链烷）的下调。值得注意的是，本质上，先天免疫系统的所有途径在衰老过程中均被上调，包括众多补体成分，参与收费样受体信号传导和炎症小体信号传导的基因，以及编码免疫球蛋白（Fc）受体和人类白细胞抗原I和II的基因。 。结论出乎意料的是，AD中先天免疫基因上调的程度相对于衰老的大脑中明显的强壮反应而言是适度的，这与在AD的最早阶段甚至在临床前阶段炎症严重参与的新观念相一致。 。最终，我们的数据表明，维持认知健康和复原力的重要策略涉及减少应在中年后期开始的慢性先天免疫激活。

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