Systemic infection modifies the neuroinflammatory response in late stage Alzheimer’s disease

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.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0592-3) contains supplementary material, which is available to authorized users.

A single systemic inflammatory insult causes acute motor deficits and accelerates disease progression in a mouse model of human tauopathy

“…Indeed, in both regions, Il1b transcription was significantly reduced in LPS‐treated P301S mice with respect to LPS‐treated controls, suggesting that microglia in the P301S model are desensitized by exposure to tau and/or degenerating neurons. Desensitization of microglia can occur upon repeated inflammatory challenge [48], and there is some evidence that microglia in humans who died with terminal systemic infections also show an immunosuppressed phenotype [49]. Moreover, in AD tissue, hippocampal microglia proximal to tau pathology showed a dystrophic or degenerative profile which was partially replicated in Thy1‐tau22, but not APP/PS1mice [50] indicating that tau does not affect microglia in the same way that amyloid‐β does.…”

“…(F) IBA1 1 cell counts in the motor cortex 24 hours after injection indicate that neither genotype nor LPS exposure significantly impacted microgliosis (C57BL/61saline n 5 6, C57BL/61LPS n 5 7, P301S1saline n 5 6, P301S1LPS n 5 6). (H) IBA1 1 cell counts in the spinal cord lamina 9 demonstrate increased microgliosis in P301S compared to control mice (1218.7 D there is some evidence that microglia in humans who died with terminal systemic infections also show an immunosuppressed phenotype [49]. Moreover, in AD tissue, hippocampal microglia proximal to tau pathology showed a dystrophic or degenerative profile which was partially replicated in Thy1-tau22, but not APP/PS1mice [50] indicating that tau does not affect microglia in the same way that amyloid-b does.…”

Lipopolysaccharide-stimulated, NF-kB-, miRNA-146a- and miRNA-155-mediated molecular-genetic communication between the human gastrointestinal tract microbiome and the brain

“…Certain strains of Bacteroidetes species such as Bacteroides fragilis (B. fragilis), as a normal commensal microbe of the human GI-tract, are thought to be ordinarily beneficial to human health due to their multiple capabilities: (i) to biosynthesize useful metabolic co-factors and products such as polysaccharides, transport proteins, volatile fatty acids and other nutrients [9,14,47,62,74]; (ii) to cleave dietary fiber into digestible short-chain fatty acids (SCFAs) that include acetate, propionate, and butyrate [9,38,63,74]; (iii) to function in the maintenance, development and homeostasis of the host immune system [14,47,62,74,79]; (iv) to support immunomodulation and protection against pathogens including potentially pathogenic GI tract bacteria [9,14,29,63,79]; and (v) to support glucose homeostasis [8,9,13,63,69,72]. Conversely, when enterotoxigenic strains of B. fragilis or their array of secretory neurotoxins leak through normally protective biophysiological-mucosal barriers they can cause substantial inflammatory pathology sys-temically that can contribute to significant mortality and morbidity [15,29,57,63,72,90]. Dietary intake of fiber may have a determinant role in regulating the composition, organization and stoichiometry of the GI-tract microbiome; for example Bacteroidetes species proliferate in porcine models fed high-fat diets that are deprived of sufficient dietary fiber [13,22,32,57,69,…”

“…Conversely, when enterotoxigenic strains of B. fragilis or their array of secretory neurotoxins leak through normally protective biophysiological-mucosal barriers they can cause substantial inflammatory pathology sys-temically that can contribute to significant mortality and morbidity [15,29,57,63,72,90]. Dietary intake of fiber may have a determinant role in regulating the composition, organization and stoichiometry of the GI-tract microbiome; for example Bacteroidetes species proliferate in porcine models fed high-fat diets that are deprived of sufficient dietary fiber [13,22,32,57,69,83,84].…”

“…It is currently not well understood if GI-tract barrier-disrupting proteolytic endotoxins such as BFT are able to propagate pathogenic actions via the systemic circulation to further disrupt the blood-brain barrier and transfer LPS, BFT, and other endotoxins into the cerebrovascular circulation to the brain parenchyma, neural cells and synaptic circuitry of the CNS. However, it has recently been reported that BF-LPS, BFT and amyloid peptides progressively alter neural cytoarchitecture, synaptic adhesion, affecting both the function and integrity of synapses -a series of processes that play critical roles in the disruption of functional inter-neuronal signaling throughout neuronal networks in AD [33,39,42,48,57,65,76].…”