Abstract
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.
Highlights
Systemic infections lead to the development of “sickness behaviour”, clinical features of which include fever, depression, apathy, self-reported ill health and attentional deficits [18]
Systemic infection did not affect the concentration of SYP or PSD95, or the ratio between these proteins, in Alzheimer’s disease (AD) (AD+ vs. AD-; Table 3)
Neuroinflammatory environment To assess the effect of systemic infection on the neuroinflammatory environment in AD, we used the MesoScale Discovery (MSD) platform to measure the levels of IFNγ, IL1β, IL2, IL4, IL6, IL8, IL10, IL12p70, IL13, TNFα, IL1α, IL5, IL7, IL12/ IL23p40, IL15, IL16, IL17A, GM-cerebrospinal fluid (CSF), TNFβ and Vascular endothelial growth factor (VEGF) in AD- and AD+ groups
Summary
Systemic infections lead to the development of “sickness behaviour”, clinical features of which include fever, depression, apathy, self-reported ill health and attentional deficits [18]. In prospective clinical studies of people with Alzheimer’s disease (AD), systemic infection with raised peripheral pro-inflammatory cytokines is associated with a marked increase in the rate of cognitive decline and in the neuropsychiatric features of sickness behaviour [29, 30]. This supports the hypothesis that microglia in the diseased brain, in a relatively benign but primed inflammatory state [55], may be activated by signalling molecules from systemic infection [59], to produce cytokines and other molecules that promote neuronal dysfunction and degeneration
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