Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study.
Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study.
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DOI：
10.1186/1742-2094-9-179
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发表时间：
2012-07-23
影响因子：
9.3
通讯作者：
Cotman CW
中科院分区：
文献类型：
--
作者：
Cribbs DH;Berchtold NC;Perreau V;Coleman PD;Rogers J;Tenner AJ;Cotman CW
本研究对衰老和阿尔茨海默病(AD)中免疫/炎症相关基因的脑基因表达谱进行了系统和全面的分析。在一项针对年轻人(20至59 岁)、老年人(60至99 岁)和阿尔茨海默病(74至95 岁)病例的强大微阵列研究中，评估了海马体、内嗅皮层、额上回和中央后回的基因反应。出现了几个新的概念。首先，在认知正常的衰老过程中，免疫/炎症相关基因的表达发生了重大变化，衰老过程中的基因反应程度远远大于AD。在芯片上询问的759个免疫相关样本中，大约40%的SFG、PCG和HC随着年龄的增长而发生显著变化，其中大多数上调(到86%)。相反，在过渡到AD的过程中，显著改变的免疫/炎症基因要少得多(约占免疫相关样本的6%)，基因反应主要限于SFG和HC。其次，无论是衰老还是AD，EC中免疫/炎症基因的显著变化相对较少，尽管EC中的许多基因在反应中表现出与其他大脑区域相似的趋势。第三，免疫/炎症基因在衰老和阿尔茨海默病中经历性别特有的反应模式，其中最显著的差异出现在衰老中。最后，在老化的大脑中，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，同时部分因子(TOLLIP，Fractalkine)下调，当这些因子出现抑制小胶质细胞/巨噬细胞激活的时候。值得注意的是，基本上所有先天免疫系统的途径在衰老过程中都被上调，包括大量补体成分、参与Toll样受体信号和炎症体信号转导的基因，以及免疫球蛋白(Fc)受体和人类白细胞抗原I和II的编码基因。出人意料的是，相对于老年脑中明显的强烈反应，AD患者先天免疫基因上调的幅度并不大，这与正在形成的观点一致，即在AD的早期阶段，甚至在临床前阶段，炎症是关键的参与其中。最终，我们的数据表明，维持认知健康和弹性的一个重要战略涉及减少慢性先天免疫激活，这应该在中年后期启动。
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). 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. 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. 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.
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影响因子：
2.9
作者：
Abe, Osamu;Yamasue, Hidenori;Ohtomo, Kuni
通讯作者：
Ohtomo, Kuni
影响因子：
5.3
作者：
Afagh, A;Cummings, BJ;Tenner, AJ
通讯作者：
Tenner, AJ
DOI：
10.1016/j.jalz.2010.12.014
发表时间：
2011-07
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Breitner JC;Baker LD;Montine TJ;Meinert CL;Lyketsos CG;Ashe KH;Brandt J;Craft S;Evans DE;Green RC;Ismail MS;Martin BK;Mullan MJ;Sabbagh M;Tariot PN;ADAPT Research Group
通讯作者：
ADAPT Research Group
影响因子：
3
作者：
Cribbs, David H.
通讯作者：
Cribbs, David H.
影响因子：
9.3
作者：
Colton CA;Mott RT;Sharpe H;Xu Q;Van Nostrand WE;Vitek MP
通讯作者：
Vitek MP