Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom.
Rejuvenation Res. 2012 Aug;15(4):395-404. doi: 10.1089/rej.2011.1302. Epub 2012 May 18.
Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample.
We measured in vivo transcript levels by microarray analysis in 691 subjects (mean age 72.6 years) in the InCHIANTI study (Invecchiare in Chianti, aging in the Chianti area). We assessed expression associations with MMSE performance at RNA collection and prior 9-year change in MMSE score in linear regression models.
In genome-wide analysis, raised CCR2 expression was cross-sectionally the most strongly associated transcript with lower MMSE score (beta=-0.16, p=5.1×10(-6), false discovery rate (FDR; q=0.077). Amongst inflammatory transcripts, only CCR2 expression was associated with both MMSE score and accelerated decline in score over the preceding 9 years (beta=-0.16, p=5.1×10(-6), q=0.003; and beta=-0.13, p=5.5×10(-5), q=0.03, respectively). CCR2 expression was also positively associated with apolipoprotein E (ApoE) e4 Alzheimer disease risk haplotype.
We show for the first time that CCR2 expression is associated with lower MMSE scores in an older human population. Laboratory models of Ccr2-mediated β-amyloid removal and regulation of neurogenesis affecting cognitive function may be applicable in humans. CCR2-mediated pathways may provide a possible focus for intervention to potentiate protective reactions to Alzheimer pathology in older people, including for people with an adverse ApoE haplotype.
循环炎症标志物在老年认知障碍中可能发挥重要作用。缺乏趋化因子（C-C 基序）受体 2（CCR2）的小鼠会发展出加速的阿尔茨海默病样病理。CCR2 对于神经发生也很重要。为了确定与简易精神状态检查（MMSE）评分最密切相关的人类基因转录本，我们在基于人群的样本的循环白细胞中进行了全基因组和炎症特异性转录组筛选。
我们通过微阵列分析测量了 InCHIANTI 研究（Invecchiare in Chianti，衰老在 Chianti 地区）中 691 名受试者（平均年龄 72.6 岁）的体内转录水平。我们在线性回归模型中评估了 RNA 采集时 MMSE 表现和之前 9 年 MMSE 评分变化的表达相关性。
在全基因组分析中，升高的 CCR2 表达与较低的 MMSE 评分最密切相关（β=-0.16，p=5.1×10(-6)，假发现率（FDR；q=0.077）。在炎症转录本中，只有 CCR2 表达与 MMSE 评分以及之前 9 年的评分加速下降相关（β=-0.16，p=5.1×10(-6)，q=0.003；β=-0.13，p=5.5×10(-5)，q=0.03）。CCR2 表达还与载脂蛋白 E（ApoE）e4 阿尔茨海默病风险单倍型呈正相关。
我们首次表明，在老年人群中，CCR2 表达与较低的 MMSE 评分相关。影响认知功能的 Ccr2 介导的β-淀粉样蛋白清除和神经发生调节的实验室模型可能适用于人类。CCR2 介导的途径可能为干预提供一个可能的焦点，以增强老年人对阿尔茨海默病病理的保护反应，包括对具有不利 ApoE 单倍型的人。
