Microglial immunophenotype in dementia with Alzheimer's pathology.
Microglial immunophenotype in dementia with Alzheimer's pathology.
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DOI：
10.1186/s12974-016-0601-z
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发表时间：
2016-06-02
影响因子：
9.3
通讯作者：
MRC CFAS
中科院分区：
文献类型：
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作者：
Minett T;Classey J;Matthews FE;Fahrenhold M;Taga M;Brayne C;Ince PG;Nicoll JA;Boche D;MRC CFAS
阿尔茨海默病的遗传风险因素表明炎症在该疾病的发展中起着因果作用。实验研究表明，小胶质细胞作为大脑巨噬细胞，具有多种功能，其在健康中的主要作用是通过高度活动的过程来调查大脑实质。利用医学研究委员会认知功能和衰老研究资源，我们对小胶质细胞进行了免疫表型分析，以研究它们在阿尔茨海默氏症病理学痴呆中的作用。通过免疫组织化学分析 299 名参与者死后获得的大脑皮层的分化簇 (CD)68（吞噬作用）、人类白细胞抗原 (HLA)-DR（抗原呈递功能）、离子钙结合接头分子 (Iba1)（小胶质细胞运动）、巨噬细胞清道夫受体 (MSR)-A（斑块相关吞噬作用）和 CD64 （免疫球蛋白 Fcγ 受体 I）。痴呆的存在与 CD68 (P < 0.001)、MSR-A (P = 0.010) 和 CD64 (P = 0.007) 呈正相关，与 Iba1 呈负相关 (P < 0.001)。在没有痴呆的参与者中，根据简易精神状态检查的认知功能与 Iba1 呈正相关（P < 0.001），与 CD68 呈负相关（P = 0.033），而在患有痴呆和阿尔茨海默病病理的参与者中，与除 Iba1 之外的所有小胶质细胞标记物呈正相关。总体而言，在没有痴呆症的参与者中，与阿尔茨海默病病理学的关系呈负相关或不显着，而在患有痴呆症和阿尔茨海默病病理学的参与者中，与阿尔茨海默病病理学的关系呈正相关。载脂蛋白 E (APOE) ε2 等位基因与 Iba1 (P = 0.001) 和 MSR-A (P < 0.001) 的表达相关，APOE ε4 与 CD68、HLA-DR 和 CD64 (P < 0.001) 的表达相关。我们的研究结果提出了一种可能性，即在阿尔茨海默病病理学痴呆中，小胶质细胞失去支持神经元所需的运动性 (Iba-1)。相反，其他小胶质细胞蛋白（CD68、MSR-A）的作用是清除受损的细胞物质，与阿尔茨海默病病理和认知功能受损呈正相关。此外，我们的数据表明，患有和不患有痴呆症的参与者中，小胶质细胞对 Aβ 和 tau 蛋白的反应可能不同，因此，正如遗传研究所支持的，小胶质细胞活动可能会影响患痴呆症的可能性，这凸显了小胶质细胞反应的复杂性和多样性。
Genetic risk factors for Alzheimer’s disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes. Using the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer’s pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for cluster of differentiation (CD)68 (phagocytosis), human leukocyte antigen (HLA)-DR (antigen-presenting function), ionized calcium-binding adaptor molecule (Iba1) (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fcγ receptor I). The presence of dementia was associated positively with CD68 (P < 0.001), MSR-A (P = 0.010) and CD64 (P = 0.007) and negatively with Iba1 (P < 0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination was associated positively with Iba1 (P < 0.001) and negatively with CD68 (P = 0.033), and in participants with dementia and Alzheimer’s pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia, the relationship with Alzheimer’s pathology was negative or not significant, and positive in participants with dementia and Alzheimer’s pathology. Apolipoprotein E (APOE) ε2 allele was associated with expression of Iba1 (P = 0.001) and MSR-A (P < 0.001) and APOE ε4 with CD68, HLA-DR and CD64 (P < 0.001). Our findings raise the possibility that in dementia with Alzheimer’s pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer’s pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to Aβ and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses.