Iba-1-/CD68+ microglia are a prominent feature of age-associated deep subcortical white matter lesions
Iba-1-/CD68+ microglia are a prominent feature of age-associated deep subcortical white matter lesions
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DOI：
10.1371/journal.pone.0210888
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发表时间：
2019-01-25
期刊：
影响因子：
3.7
通讯作者：
Highley, J. Robin
中科院分区：
文献类型：
--
作者：
Waller, Rachel;Baxter, Lynne;Highley, J. Robin
大脑皮层下深层病变（DSCL）存在于大约60%的老年人口中，并与认知能力下降和抑郁症有关。DSCL与脱髓鞘、血脑屏障（BBB）功能障碍和小胶质细胞增生有关。小胶质细胞是大脑的主要免疫细胞。在生理条件下，小胶质细胞具有分支形态，并且对病理反应具有更圆的形态变化以及显示蛋白质表达改变。本研究建立在先前DSCL的特征和放射学上“正常”的白质（NAWM）的基础上，通过对一系列小胶质细胞标记物和血管完整性标记物进行详细的表征。认知功能和衰老研究（CFAS）提供了对照白质（WM）、NAWM和DSCL人死后组织，使用小胶质细胞标志物（Iba-1、CD68和MHCII）、血管基底膜标志物（胶原IV）和血脑屏障完整性标志物（纤维蛋白原和水通道蛋白4）进行免疫组化。CD68的免疫反应谱从对照wm到NAWM再到DSCL逐步增加。这与小的、分叉的细胞向更大、更圆的小胶质细胞的转变有关。虽然与对照组相比，NAWM中Iba-1的免疫反应性更高，但在DSCL中，Iba-1水平降至对照组水平。这些DSCL的一个突出特征是Iba-1(-)/CD68（+）小胶质细胞群。IV型胶原增加，但血脑屏障完整性没有改变。总的来说，研究显示小胶质细胞标记物的免疫反应谱有显著差异。这是病变发展的原因还是结果还有待阐明。基于形态学和分子标记识别小胶质细胞亚群可能最终有助于破译它们在神经变性中的功能和作用。此外，本研究表明Iba-1不是泛小胶质细胞标记物，需要几种小胶质细胞标记物的组合才能充分表征小胶质细胞表型。
Deep subcortical lesions (DSCL) of the brain, are present in similar to 60% of the ageing population, and are linked to cognitive decline and depression. DSCL are associated with demyelination, blood brain barrier (BBB) dysfunction, and microgliosis. Microglia are the main immune cell of the brain. Under physiological conditions microglia have a ramified morphology, and react to pathology with a change to a more rounded morphology as well as showing protein expression alterations. This study builds on previous characterisations of DSCL and radiologically 'normal-appearing' white matter (NAWM) by performing a detailed characterisation of a range of microglial markers in addition to markers of vascular integrity. The Cognitive Function and Ageing Study (CFAS) provided control white matter (WM), NAWM and DSCL human post mortem tissue for immunohistochemistry using microglial markers (Iba-1, CD68 and MHCII), a vascular basement membrane marker (collagen IV) and markers of BBB integrity (fibrinogen and aquaporin 4). The immunoreactive profile of CD68 increased in a stepwise manner from controlWM to NAWM to DSCL. This correlated with a shift from small, ramified cells, to larger, more rounded microglia. While there was greater Iba-1 immunoreactivity in NAWM compared to controls, in DSCL, Iba-1 levels were reduced to control levels. A prominent feature of these DSCL was a population of Iba-1(-)/CD68(+) microglia. There were increases in collagen IV, but no change in BBB integrity. Overall the study shows significant differences in the immunoreactive profile of microglial markers. Whether this is a cause or effect of lesion development remains to be elucidated. Identifying microglia subpopulations based on their morphology and molecular markers may ultimately help decipher their function and role in neurodegeneration. Furthermore, this study demonstrates that Iba-1 is not a pan-microglial marker, and that a combination of several microglial markers is required to fully characterise the microglial phenotype.