Centre for Free Radical Research, University of Otago, Christchurch, New Zealand.
Department of Pathology and Biomedical Science, University of Otago, PO Box 4345, Christchurch, 8140, New Zealand.
Acta Neuropathol Commun. 2022 Mar 24;10(1):38. doi: 10.1186/s40478-022-01347-2.
Neutrophil accumulation is a well-established feature of Alzheimer's disease (AD) and has been linked to cognitive impairment by modulating disease-relevant neuroinflammatory and vascular pathways. Neutrophils express high levels of the oxidant-generating enzyme myeloperoxidase (MPO), however there has been controversy regarding the cellular source and localisation of MPO in the AD brain.
We used immunostaining and immunoassays to quantify the accumulation of neutrophils in human AD tissue microarrays and in the brains of APP/PS1 mice. We also used multiplexed immunolabelling to define the presence of NETs in AD.
There was an increase in neutrophils in AD brains as well as in the murine APP/PS1 model of AD. Indeed, MPO expression was almost exclusively confined to S100A8-positive neutrophils in both human AD and murine APP/PS1 brains. The vascular localisation of neutrophils in both human AD and mouse models of AD was striking and driven by enhanced neutrophil adhesion to small vessels. We also observed rare infiltrating neutrophils and deposits of MPO around plaques. Citrullinated histone H3, a marker of neutrophil extracellular traps (NETs), was also detected in human AD cases at these sites, indicating the presence of extracellular MPO in the vasculature. Finally, there was a reduction in the endothelial glycocalyx in AD that may be responsible for non-productive neutrophil adhesion to the vasculature.
Our report indicates that vascular changes may drive neutrophil adhesion and NETosis, and that neutrophil-derived MPO may lead to vascular oxidative stress and be a relevant therapeutic target in AD.
中性粒细胞的积累是阿尔茨海默病（AD）的一个既定特征，通过调节与疾病相关的神经炎症和血管途径，与认知障碍有关。中性粒细胞表达高水平的氧化酶髓过氧化物酶（MPO），然而，关于 MPO 在 AD 大脑中的细胞来源和定位一直存在争议。
我们使用免疫染色和免疫测定来量化人 AD 组织微阵列和 APP/PS1 小鼠大脑中中性粒细胞的积累。我们还使用多重免疫标记来定义 AD 中 NET 的存在。
AD 大脑以及 AD 的 APP/PS1 小鼠模型中中性粒细胞增加。事实上，在人 AD 和鼠 APP/PS1 大脑中，MPO 表达几乎完全局限于 S100A8 阳性中性粒细胞。中性粒细胞在人 AD 和 AD 小鼠模型中小血管中的血管定位引人注目，这是由中性粒细胞对小血管的粘附增强驱动的。我们还观察到罕见的浸润性中性粒细胞和 MPO 围绕斑块沉积。在这些部位，也在人类 AD 病例中检测到中性粒细胞细胞外陷阱（NETs）的标志物瓜氨酸化组蛋白 H3，表明血管中存在细胞外 MPO。最后，AD 中内皮糖萼减少，这可能是导致中性粒细胞与血管非生产性粘附的原因。
我们的报告表明，血管变化可能导致中性粒细胞粘附和 NETosis，而中性粒细胞衍生的 MPO 可能导致血管氧化应激，并成为 AD 的一个相关治疗靶点。
