Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
Dementia Research Group, University of Bristol Medical School, Learning & Research, Southmead Hospital, Bristol, UK.
Acta Neuropathol Commun. 2018 Sep 7;6(1):88. doi: 10.1186/s40478-018-0592-3.
Clinical studies indicate that systemic infections accelerate cognitive decline in Alzheimer's disease. Animal models suggest that this may be due to enhanced pro-inflammatory changes in the brain. We have performed a post-mortem human study to determine whether systemic infection modifies the neuropathology and in particular, neuroinflammation, in the late-stage of the disease.Sections of cerebral cortex and underlying white matter from controls and Alzheimer's patients who died with or without a terminal systemic infection were immunolabelled and quantified for: (i) Αβ and phosphorylated-tau; (ii) the inflammation-related proteins Iba1, CD68, HLA-DR, FcγRs (CD64, CD32a, CD32b, CD16), CHIL3L1, IL4R and CCR2; and (iii) T-cell marker CD3. In Alzheimer's disease, the synaptic proteins synaptophysin and PSD-95 were quantified by ELISA, and the inflammatory proteins and mRNAs by MesoScale Discovery Multiplex Assays and qPCR, respectively.Systemic infection in Alzheimer's disease was associated with decreased CD16 (p = 0.027, grey matter) and CD68 (p = 0.015, white matter); increased CD64 (p = 0.017, white matter) as well as increased protein expression of IL6 (p = 0.047) and decreased IL5 (p = 0.007), IL7 (p = 0.002), IL12/IL23p40 (p = 0.001), IL15 (p = 0.008), IL16 (p < 0.001) and IL17A (p < 0.001). Increased expression of anti-inflammatory genes CHI3L1 (p = 0.012) and IL4R (p = 0.004) were detected in this group. T-cell recruitment to the brain was reduced when systemic infection was present. However, exposure to systemic infection did not modify the pathology. In Alzheimer's disease, CD68 (p = 0.026), CD64 (p = 0.002), CHI3L1 (p = 0.016), IL4R (p = 0.005) and CCR2 (p = 0.010) were increased independently of systemic infection.Our findings suggest that systemic infections modify neuroinflammatory processes in Alzheimer's disease. However, rather than promoting pro-inflammatory changes, as observed in experimental models, they seem to promote an anti-inflammatory, potentially immunosuppressive, environment in the human brain.
临床研究表明，全身感染会加速阿尔茨海默病患者的认知能力下降。动物模型表明，这可能是由于大脑中促炎变化增强所致。我们进行了一项死后人体研究，以确定全身感染是否会改变疾病晚期的神经病理学，特别是神经炎症。我们对来自对照组和死于全身感染或无全身感染的阿尔茨海默病患者的大脑皮质和下白质切片进行免疫标记和定量：（i）β淀粉样蛋白和磷酸化tau；（ii）炎症相关蛋白 Iba1、CD68、HLA-DR、FcγRs（CD64、CD32a、CD32b、CD16）、CHIL3L1、IL4R 和 CCR2；和（iii）T 细胞标记物 CD3。在阿尔茨海默病中，通过 ELISA 定量突触蛋白突触素和 PSD-95，通过 MesoScale Discovery Multiplex 测定法和 qPCR 分别定量炎症蛋白和 mRNAs。阿尔茨海默病患者的全身感染与 CD16 减少有关（p = 0.027，灰质）和 CD68（p = 0.015，白质）；CD64 增加（p = 0.017，白质）以及 IL6 蛋白表达增加（p = 0.047）和 IL5 减少（p = 0.007）、IL7（p = 0.002）、IL12/IL23p40（p = 0.001）、IL15（p = 0.008）、IL16（p < 0.001）和 IL17A（p < 0.001）。在该组中还检测到抗炎基因 CHI3L1（p = 0.012）和 IL4R（p = 0.004）的表达增加。当存在全身感染时，T 细胞向大脑的募集减少。然而，全身感染并不会改变病理学。在阿尔茨海默病中，CD68（p = 0.026）、CD64（p = 0.002）、CHI3L1（p = 0.016）、IL4R（p = 0.005）和 CCR2（p = 0.010）的表达增加与全身感染无关。我们的研究结果表明，全身感染会改变阿尔茨海默病患者的神经炎症过程。然而，与实验模型中观察到的促炎变化不同，它们似乎在人类大脑中促进抗炎、潜在的免疫抑制环境。
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