期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s40478-018-0592-3
关键词
Alzheimer's disease; Systemic infection; Neuroinflammation; Human brain; Microglia
资金
- Alzheimer's Research UK [ARUK-PG2012-8]
- MRC [MR/N004272/1, MC_PC_18025, G0701018, MR/M024784/1, G1100578, MC_PC_14095] Funding Source: UKRI
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 postmortem 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) A beta and phosphorylated-tau; (ii) the inflammation-related proteins Iba1, CD68, HLA-DR, FcyRs (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), IL12/1L23p40 (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.
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