Iron loading is a prominent feature of activated microglia in Alzheimer's disease patients.
Iron loading is a prominent feature of activated microglia in Alzheimer's disease patients.
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DOI：
10.1186/s40478-021-01126-5
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发表时间：
2021-02-17
影响因子：
7.1
通讯作者：
van der Weerd L
中科院分区：
文献类型：
--
作者：
Kenkhuis B;Somarakis A;de Haan L;Dzyubachyk O;IJsselsteijn ME;de Miranda NFCC;Lelieveldt BPF;Dijkstra J;van Roon-Mom WMC;Höllt T;van der Weerd L
大脑铁积累已被发现加速淀粉样蛋白β(Aβ)阳性阿尔茨海默病患者的疾病进展，尽管其机制仍不清楚。小胶质细胞已被确定为该病发病机制中的关键分子，是对铁水平升高等异常做出反应的高反应细胞。因此，我们利用组织学方法、多光谱免疫荧光和自行开发的自动小胶质细胞分割和分析流水线，研究了人类阿尔茨海默病脑内积铁小胶质细胞的存在及其对其激活状态的影响。我们发现了一组小胶质细胞，铁储存蛋白铁蛋白轻链(FTL)的表达增加，Iba1的表达增加，TMEM119和P2RY12的表达降低。激活的小胶质细胞亚群代表积铁的小胶质细胞，在形态上表现为营养不良。多光谱免疫荧光可对FTL+IBA1+-小胶质细胞进行空间分析，发现它们是主要的Aβ斑块浸润性小胶质细胞。在高Aβ负荷和高Tau负荷的患者中，FTL+IBA1+-小胶质细胞增多。这些发现提示铁被小胶质细胞摄取，并影响这些细胞的功能表型，特别是与Aβ结合时。
Brain iron accumulation has been found to accelerate disease progression in amyloid-β(Aβ) positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological methods, multispectral immunofluorescence and an automated in-house developed microglia segmentation and analysis pipeline, we studied the occurrence of iron-accumulating microglia and the effect on its activation state in human Alzheimer brains. We identified a subset of microglia with increased expression of the iron storage protein ferritin light chain (FTL), together with increased Iba1 expression, decreased TMEM119 and P2RY12 expression. This activated microglia subset represented iron-accumulating microglia and appeared morphologically dystrophic. Multispectral immunofluorescence allowed for spatial analysis of FTL+Iba1+-microglia, which were found to be the predominant Aβ-plaque infiltrating microglia. Finally, an increase of FTL+Iba1+-microglia was seen in patients with high Aβ load and Tau load. These findings suggest iron to be taken up by microglia and to influence the functional phenotype of these cells, especially in conjunction with Aβ.
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